I beg to move, in page 5, line 45, at the end, to add: (2) The Secretary of State may from time to time by order direct that the foregoing subsection shall have effect, in relation to houses approved by him for the purposes of the last foregoing section after the date on which the order comes into force, as if for the reference to an amount equal to the contributions so payable by the Secretary of State as aforesaid there were substituted a reference to an amount bearing such proportion to the said contributions as may be specified in the order. An order of the Secretary of State under this subsection shall be of no effect until it is approved by a resolution of the Commons House of Parliament. Under Clause 5, as drafted, a local authority which is receiving an Exchequer contribution under Clause 4 is required to make an equivalent contribution from the rates; that is to say, its contribution is 50 per cent, and the Exchequer contribution is 50 per cent. The Amendment I am now moving will enable the Secretary of State to vary these proportions by order, and I am moving it to meet views which have been expressed by hon. Members that there should be power to alter the ratio by order, rather than by going through the whole process of legislation. To be effective, the order would require to be approved by this House by affirmative Resolution.
I should make it clear that it is not contemplated that any action is necessary in the near future, but circumstances which are at present unforeseen may arise which would make it desirable to vary the ratio, and for that reason the Government decided to put down this Amendment. While I agree that there 1767 is no obligation upon us slavishly to follow in the footsteps of my right hon. Friend the Minister of Housing and Local Government, my right hon. Friend agreed, in dealing with a similar Bill for England and Wales, to put down an Amendment similar to this one when that Bill was reconsidered in Committee before the Report stage was commenced. That Amendment was accepted. I felt, therefore, that it probably would meet the views of many hon. Members to table a similar Amendment. I hope that it will be acceptable to the Committee.
The last part of the speech of the Secretary of State for Scotland gave us rather a cold douche. At first he told us that the Amendment was put forward in order to meet arguments raised by my hon. Friends, but he finished by telling us that it was put forward because his right hon. Friend had made alterations in the English Bill. We are therefore not very clear about the purpose or the origin of the Amendment.
In any case, we have a further disappointment. In moving the Amendment the right hon. Gentleman has not deleted Clause 5 as at present drafted. Our objections were mainly to the fact that the proportion was quite wrong and that the local authorities considered that the proportion should be 1 to 3, as in all other housing grants. We seem to be following the pattern of Clause 4 to which the present Clause refers. Clause 4 starts by being very definite that £7 5s. is to be paid over 15 years. That sounds very promising, but we find that the first proviso says: Provided that the Secretary of State may from time to time by order direct that paragraph (b) of this subsection shall have effect, in relation to houses approved after the date on which the order comes into force, as if for the sum therein specified there were substituted such higher or lower sum as may be specified in the order. We start with the declaration that the grant is to be £7 5s., then the Secretary of State reserves his right to make it what he likes.
We pass on to subsection (3), where again the Secretary of State takes power to alter contributions to a local authority. In fact, at the end of the subsection he may withhold the whole or any part of the contributions payable under 1768 that subsection to a local authority. We have never got satisfaction as to what this means. The Secretary of State has power not to pay anything to a local authority.
When we come to Clause 5, we get a curious situation. The local authority must pay an equal proportion to that which the Government pay. The Government, in Clause 4 (3), may withhold the whole of their contribution to the local authority, and the local authority's contribution in that event may be 50 per cent, of nothing. In other words, it will be allowed to spend nothing.
In the subsection now being moved, the Secretary of State introduces a new flexibility into Clause 5. If Clause 5 had been withdrawn and the Secretary of State had proposed a new Clause to give him power to make a proportionate grant according to what he specified in an order to be brought before the House, that would at least have given a promise that the local authorities could discuss the proportion with him in the future. He now tells us that the proposed new subsection means nothing at all, and that, although he is putting it forward, nothing is proposed to be done under it unless unforeseen circumstances arise. He has not told us what kind of circumstances may arise.
Anyone who reads the Bill to find out the position of a local authority under it will be in a complete maze. To start with. Clause 4 gives a calculation that local authorities will get £7 5s. and then finishes by saying that they will not get £7 5s. In the next subsection we find that the local authorities may not get anything at all. Under Clause 5, local authorities are to pay the same contribution as the State, namely, 50 per cent., but in the new subsection they will be paid only according to the whim of the Secretary of State.
Are the Government going to pay the grant or not? What does the Amendment mean? Does it mean that the local authorities are to have a bigger proportion than 50 per cent., or that the Secretary of State will agree in future to the request of the local authorities that the grant under this Clause should be on the same 3-to-l basis as in all other housing legislation and not 50–50? 1769 The Secretary of State ought to give us more illumination on these matters. I do not know whether he has copied these provisions automatically from his right hon. Friend, but he ought to clarify the position for the local authorities before we pass from the Clause.
I listened most carefully to the Secretary of Stale when he was moving the Amendment. He did not tell us very much. Clause 5 is very short, and we must have regard to what is laid down in Clause 4. I do not know whether the Secretary of State is proposing the Amendment only because of what the Minister of Housing and Local Government did in the English Bill. If so, can the right hon. Gentleman tell the Committee whether the English Bill contains provisions similar to Clause 4?
Clause 4 gives the Secretary of State all the power he is asking for in the Amendment. If we look at subsection (2) we see a proviso which reads: Provided that the Secretary of State may from time to time by order direct that paragraph (b) of this subsection shall have effect, in relation to houses approved after the date on which the order comes into force, as if for the sum therein specified there were substituted such higher or lower sum as may be specified in the order. Surely ample power is there either way, if things do not go how the Secretary of State envisages they should go.
If the right hon. Gentleman wants to make headway with this matter, he ought to say that local authority expenditure may become so high that the proposed 50 per cent, proportion is not enough and that the purpose of the Amendment is to increase the Government's subsidy to local authorities; in other words, that the local authorities are to be given more than £7 5s. in subsidy from the Government. I really cannot understand the position. The right hon. Gentleman should tell us something more than just that, as the English Minister has put this provision in the English Bill, we should put it in the Scottish version.
What is the right hon. Gentleman's fear? Are the powers in Clause 4 not sufficient already? When the provision I have read out gives him permission to increase or lower, why does he need this further provision in Clause 5, which deals with the same thing? It is one thing to say that, due to rising costs and increased expenditure, he feels that local authorities 1770 tackling the problem realistically will be hard pressed and that he wants reserve powers to increase the Government's ratio to more than 50 per cent. But if it means that he wants the local authorities possibly to pay more when already under the provisions of the Bill they will be saddled with a fearsome burden, then we on this side have no sympathy with the Amendment.
A little further explanation is required of the Government here. As my right hon. Friend the Member for East Stirlingshire (Mr. Woodburn) has pointed out, local authorities must know how they stand financially in these matters. If in forcing local authorities into a task which to most of them is distasteful and fairly costly the Government said, "Do not worry; for 15 years we will give you £7 5s. for each house you patch up," and, in a further Clause," You will pay exactly the same as us," the local authorities would then know exactly their own financial obligations.
In Clause 4, however, the Government say that they will be able to vary up or down the amount they pay to the local authorities over the 15 years. From the point of view of the local authorities, that is uncertain enough—I am sure no businessman on the other side would like to be left in such a state of financial uncertainty—but now this Clause introduces something new.
Why retain a figure like that?
I have to start with some proposed figure and the amount is referred to in Clause 4 (2, b) of the Bill. The Government could reduce their own 1771 contribution to £6 but, under the subsection with which we are now dealing, they could compel the local authority to pay £8 10s. instead of £7 5s. The local authority is put in a very difficult position, and I think we should have from the Secretary of State an explanation of what he has in mind. If there is one thing about which burgh treasurers in Scotland are concerned, it is the money and where it is to come from. They are very grateful for increased contributions coming from the Exchequer, but here they can be financially dictated to.
The Joint Under-Secretary of State preaches to us and says, "Please leave the local authorities alone." He now says, "We want the power to dictate to the local authorities that they shall pay more than the 50 per cent, that the Government are paying." That can go on for 15 years. It will be 15 years of financial chaos. The only hope is that this Government will be out of office within 15 months and not 15 years.
I flattered myself that I understood the ramifications of this Bill, but I must now confess that the Amendment which the right hon. Gentleman has proposed makes it more complex than ever it was before. I should like to know, for example, whether the Amendment will now cover houses compulsorily purchased by local authorities, those purchased by agreement, those already in the possession of local authorities under the Town and Country Planning Act—even those houses which have been gifted to local authorities. Does the proposed Amendment embrace all those houses, and the houses coming under the Act as a whole?
Will the proposed Amendment alter the basis of an annual payment equal to one half of the annual loan charges as distinct from the annual payment of the contributions of £7 5s. by the Government and by the local authority? If so, it will be a very serious matter for the local authority. It will be very difficult for a local authority to understand quite clearly what the financial implications of this Bill now are.
I should like to know how the Lord Advocate is able to square up the proposed Amendment with Clause 4 (3), which states: 1772 If it appears to the Secretary of State that the expenditure incurred as a whole by a local authority in carrying out works on houses approved by the Secretary of State for the purposes of this section is unduly low having regard to the amount of the contribution for the time being payable in respect of those houses under paragraph (b) of subsection (2) of this section, he may withhold the whole or any part of the contributions payable under that paragraph to that authority. Clause 5, with the proposed Amendment, would read: as if for the reference to an amount equal to the contributions so payable by the Secretary of State as aforesaid there were substituted a reference to an amount bearing such proportion to the said contributions as may be specified in the order. 7.30 p.m.
The Secretary of State is taking right and power from every conceivable angle. He is to withhold, to alter, to substitute, to give an unknown contribution, he is going to put it up or down. He cannot play that sort of Jekyll and Hyde game with the local authorities, and I ask the right hon. Gentleman to come clean. This Amendment makes this an insidious Clause. The right hon. Gentleman must come clean with the local authorities, and let them know precisely where they stand.
I ask the Minister to take back Clauses 4 and 5 for reconsideration. I do not know whether it is the Parliamentary draftsmen who are responsible for this. If it is, it is not to their credit. However, the right hon. Gentleman cannot escape responsibility on that score, and I ask him to take the Amendment back and redraft it, and bring it forward again on Report. I do so in the interests of the local authorities, and, indeed, in the interests of the Government themselves.
With further reference to what my hon. Friend the Member for Glasgow, Central (Mr. McInnes) has just said, I should like the right hon. Gentleman to read the preceding Clause, particularly the proviso to subsection (2). He will find that the idea that he seeks to introduce into this Clause is dealt with there. By proposing this new subsection he is introducing what, so far as this Clause is concerned, is a new idea, and he is thereby introducing into the administration of the Measure uncertainty, complication and complexity. He will make the Bill difficult to construe and difficult to administer.
1773 By this new subsection he is providing for two sets of houses, two different types, one under subsection (1) and the other under subsection (2). In what circumstances, to use the language of the Amendment, are the houses to be "approved by him "? What rules are to be made for his approval? How is he to discriminate one set of houses from the other? Will not all this complication greatly increase the responsibilities of the local authorities and make it necessary for them to increase their staffs and increase their expenses and put an added and quite unnecessary burden on the ratepayers? I sincerely hope the Government will take the new Clause back and reconsider it, and send it to limbo.
The hon. and learned Gentleman the Member for Aberdeen, North (Mr. Hector Hughes) said that he hoped we would take the new Clause back, but I am dealing with an Amendment to Clause 5. There is no sinister motive connected with the Amendment whatsoever. I can assure the Committee of that. I am rather disappointed and surprised that it has received such a lukewarm reception. I had hoped it might have been accepted, because when the English Measure was recommitted and the Government moved a similar Amendment, the Opposition spokesman said: I take the opportunity of thanking— the Government— —for this concession to local authorities."— [OFFICIAL REPORT, 31st March, 1954; Vol. 5,25, c. 2074.] It was apparently something that was wanted.
I said, in reply to the right hon. Gentleman, that we are not contemplating at this stage varying the ratio, which is 50–50. I said in moving the Amendment that unforeseen circumstances might occur which would make some alteration necessary or desirable. I am not aware of that at this stage. Parliamentary control is retained because any change can be made only by making an order and laying that order and getting an affirmative Resolution. That provision retains Parliamentary control. The short answer, therefore, to the hon. Member for Central Ayrshire (Mr. Manuel) is that it would require legislation to vary the ratio in the Bill, and the object of the Amendment is to make it possible to 1774 vary the ratio by an order and affirmative Resolution. The Government have accepted the view that this is a simplification of procedure. It appeared to be one that was welcomed by the Opposition in connection with the English Bill. That was why I put down this Amendment. There is no sinister motive behind it.
I think the answer to the hon. Member for Kilmarnock (Mr. Ross) is that Parliamentary control is retained. The answer to the hon. Member for Glasgow, Central (Mr. McInnes) is that Clause 4 enables the Secretary of State to increase the contribution of £7 5s. should it be desirable, but Clause 5 as it stands does not permit of any alteration in the ratio. There is nothing about this Amendment that need alarm anybody, and I hope the Committee will accept it.
I explained that if this Amendment had the purpose of setting the right hon. Gentleman free to consider the local authorities' desire that the ratio should be altered to 1 to 3 rather than 50–50, we should be prepared to accept it, and might even be prepared to welcome it. We are probably a little more cautious than our English colleagues in welcoming it. That is not because we think the right hon. Gentleman is full of sinister thoughts. Indeed, one of our difficulties is that we are not clear what he has in mind about the matter, or whether he has any thoughts of what will happen. When he moved the Amendment he appeared to have no purpose, except, perhaps, to obtain greater latitude to change his mind lest something should turn up that would require him to do so.
We are all in favour of the Secretary of State having power, but it would have been more satisfactory if the right hon. Gentleman had been able to tell us a little more of what this is all about. After moving the Amendment he proceeded to explain that he had no knowledge of any circumstances in which the Amendment would come into force.
I think the Lord Advocate must agree that the people who have to work the Measure should be able to get some logic out of it. It may be that we Scots are a bit weak in insisting on there being any logic in it, when our English colleagues, perhaps, would not insist on it. They are prepared to accept what they regard as common sense, and hope that it will work 1775 out all right in the end. We are a little bit more realistic. The Lord Advocate is supposed to advise us on the legal aspects of the matter, and therefore I would ask him how the Clause can be reconciled with Clause 4 (3).
If 50–50 is the rule and remains the rule, how can the Secretary of State take away his 50 if the Clause says that payments must be 50–50 as between the local authority and the Secretary of State? If they are to be equal payments by both the local authority and the Secretary of State, how can this be reconciled with the power in subsection (3) of Clause 4 that after the local authority has spent its 50, the Secretary of State may take his 50 back again and withhold it? It seems to me quite irreconcilable.
I wish that the Secretary of State would try to get some sort of harmony in the Bill and some kind of pattern that local authorities can understand. There may be something wrong with my mind, but I cannot understand the Clause and I have not heard of any local authority which understands its position. Now the right hon. Gentleman says that he will make the Clause more flexible and bring it before the House, which is quite a good thing, but I should be more satisfied if he withdrew the Clause and left it for the Secretary of State to introduce an order saying what proportions were to be used in regard to these payments, and if he gave the assurance that this matter would be discussed with the local authorities and that if they showed good cause for altering the proportion, the right hon. Gentleman would be willing to consider it.
We do not think that the right hon. Gentleman has any sinister intentions—in fact, we are convinced by what he says that he has no intentions either sinister or otherwise; but it would be more satisfactory for the Committee, in agreeing to the Amendment, if Members knew that it had some purpose and that that purpose would be carried out.
I asked the Secretary of State whether the powers contained in Clause 4 were not sufficient without his Amendment to Clause 5, and the right hon. Gentleman replied that without the Amendment legislation would be necessary- But the portion of the Amendment 1776 to which the right hon. Gentleman has referred states: An order of the Secretary of State under this subsection shall be of no effect until it is approved by a resolution of the Commons House of Parliament. Clause 4 (4) states: An order of the Secretary of State under subsection (2) of this section shall be of no effect until it is approved by a resolution of the Commons House of Parliament. That is exactly the same thing. The Secretary of State already has in Clause 4 what he said he did not have in Clause 5. The words which I have quoted are identical. The right hon. Gentleman cannot ride off in that way.
What is the explanation? I am sure that the Secretary of State did not deliberately fob me off, and must have overlooked these identical words. If he reads Clause 4 (4) and then the latter part of his Amendment, the words of which are identical, he will see that his reply was wrong and that the Amendment is quite unnecessary.
Will the Secretary of State answer the point made by my hon. Friend the Member for Glasgow, Central (Mr. McInnes) regarding the varying of the ratio, which applies not only to subsection (2, a) of Clause 4 but to subsection (2, b)?
I do not want to hide anything at all. We have passed Clause 4, in which the Secretary of State is enabled to increase the £7 5s. contribution.
To vary it. Clause 5 does not give the Secretary of State power to vary the amount which is to be paid— the 50–50 ratio in the Bill.
The right hon. Gentleman is quite wrong.
The sole object of the Amendment is to enable the ratio—at present the 50–50, which is the figure decided on—to be varied should circumstances in the future make it desirable to do so without coming to the House for legislation. It is purely a simplification which, as I said, I hoped would be acceptable to the Committee.
I may be completely wrong, but I seem to be in fairly general 1777 company. When we discussed this matter in Standing Committee, the Joint Undersecretary replied. My recollection is that we were told that the power to vary, to which the right hon. Gentleman has referred and which arises from Clause 4 (3), had to exist because there might come a time when circumstances had changed and the position had to be reviewed. The Committee were not very happy about that, I agree.
Possibly I am misunderstanding the right hon. Gentleman's intention. It may be that he is seeking to rid himself of that arbitrary power, and that he is proposing to substitute for that arbitrary power in Clause 4 this more limited power which, as he says, would rest on an Affirmative Resolution of the House. It is a little disturbing with this type of machinery that such an order would not be amendable, but would have to be accepted or rejected; but it might be argued that that was a step forward.
It may be that it would be the right hon. Gentleman's intention not to vary the situation and not in any way to place a greater burden upon the local authority without first coming to the House; but the right hon. Gentleman must explain why I and my hon. Friends are completely misunderstanding the situation and that if this is the only method he would use, he will take powers at a later stage to rid himself of the greater and overriding power. It is difficult to understand his argument.
Even if the right hon. Gentleman were able to meet us there, the difficulty would still exist that no local authority can plan if it does not know from year to year what financial burden it has to bear and what part is being shared by the Treasury. If the right hon. Gentleman would say that he does not contemplate any circumstance in which the ratio could be varied to the prejudice of the local authority, we would be taking a big step forward. To be fair to him, he seems to have that in mind and came near to saying it in reply to my right hon. Friend the Member for East Stirlingshire (Mr. Woodburn).
The Secretary of State said clearly that in the later discussions with the local authorities he had carried them with him in the sense that they did not object to the ratio, although they might object to the basis of the calculation. It would be extremely unfortunate if now the right 1778 hon. Gentleman threw away that measure of good will which he secured by his negotiations subsequent to the Second Reading of the Bill.
Will he not, therefore, say that he will look again to see whether there is substance in the argument which I am offering, and which several of my hon. Friends share, that he seems to have two powers, one of which overrides the limited power, and that if there is anything in our suggestion he will find a revised form of words? If I am wrong in my understanding of the matter—and I am inclined to be honest and imagine that I am misunderstanding the situation—perhaps I can be corrected. Parliamentary draftsmen occasionally leave loopholes and the best of them produce ambiguities, but they do not produce a flat contradiction, so I am inclined to argue that I must be misunderstanding the situation.
Apart from that, now is the time for the right hon. Gentleman to say that he seeks this Amendment only so that the ratio may be varied to the benefit of the local authority and never to its disadvantage. If it could be to its disadvantage, we may have something to say about the previous Clause, but it would greatly facilitate the proceedings of the Committee and relieve many of the anxieties of local authorities if we could have from the right hon. Gentleman the assurance which we seek.
I can give this assurance to the right hon. Gentleman, that there is absolutely no intention of altering the present 50–50 ratio. That is not at the back of the Government's mind. What was proposed by my right hon. Friend the Minister of Housing and Local Government during the Committee stage of the Housing Repairs and Rents Bill was that the Government should have a more flexible implement to deal with such matters as this. I say there is no intention at the present time of altering the ratio, and I can give the right hon. Gentleman the assurance, if it is of any satisfaction to him and the Committee— we are anxious to proceed with the rest of this Bill—that there will be no alteration during the lifetime of the present Parliament and before a General Election has taken place.
I wonder whether the right hon. Gentleman is now trying to pull 1779 my leg? Can anything more alarming to the local authorities in Scotland be imagined than to be solemnly told that this 15-year plan, this "Operation Rescue "on a massive scale is going to be valid only for an additional 2½years? Let us assume that it will be a year before plans are approved. That, I think, was the suggestion of the right hon. Gentleman in Standing Committee. In those circumstances local authorities may not be able to start operations until the following year, that is to say, 1956. The undertaking which the right hon. Gentleman now gives could mean that the local authorities would never once hope to have this 50–50 ratio maintenance.
I do not think the right hon. Gentleman means that. He does not intend to inflict further hardship on the local authorities by reducing the ratio. But if he did not mean that, he must, to ease the mind of not only the Committee but also the local authorities, say that not for the next five, seven or 10 years does he contemplate varying the ratio adversely to the local authorities. Speaking for the Opposition, and indeed for the next most likely Government, I can say that we certainly would never use this machinery to prejudice the local authorities. If I can say that, surely the right hon. Gentleman, who no doubt has been contemplating the electoral results announced last week and assuming that they might apply to himself, can fairly say that there will be no change to the disadvantage of the local authorities.
As I have failed to satisfy the right hon. Gentleman and the Committee with an Amendment which I thought was going to be acceptable, and because of the debate that has taken place, I beg to ask leave to withdraw the Amendment.
I will be quite frank with the right hon. Gentleman. I am on my feet so that my hon. Friends may have an opportunity of considering whether the suggestion of the right hon. Gentleman to withdraw this Amendment is a wise one or whether we ought to press the Secretary of State and the Government to divide upon the issue. As I stand here at this Box, I am not at all clear in my mind which is the correct course to take.
1780 What is it that the right hon. Gentleman argues? He argues that, because we have been concerned for the welfare of the local authorities and have been anxious to discover whether this Amendment could be used to their disadvantage, he should withdraw his Amendment. He is overwhelmed by the arguments which we have put forward. [HON. MEBMERS: "Oh."] There are only two explanations. One is that the right hon. Gentleman anticipated using this power to make an order so that the local authorities might be advantaged. If I had been in his position and that had been my intention, I would have said so to the Committee, and if he had said so my hon. and right hon. Friends would immediately have approved the intention. But it seems that the right hon. Gentleman is not able to give such an undertaking on behalf of the Government.
That means that this new ratio of 50–50 is the most the Government will do. It takes the place of the rate of 3 to 1 in favour of the Government and is the most the right hon. Gentleman is prepared to make. But he says to himself, "The opposition is so strong to this that I really will be in trouble with the local authorities over their interpretation of this Amendment, which might mean that their future was even less securely safeguarded. I think, therefore, that it is an advantage and a distinct score at the Opposition to withdraw this Amendment."
The right hon. Gentleman has asked leave to withdraw his Amendment, and I must now put the Question.
Is it not possible to argue whether the Amendment should be withdrawn or not?
Not now, but the Amendment can still be debated.
I am not treating the Committee with discourtesy at all. I am endeavouring to please the Committee by withdrawing an Amendment which it does not seem to like.
The Committee has not raised the slightest objection to the Amendment. Indeed, I stated categorically that what we would regret was if the Secretary of State did not withdraw Clause 5 and bring in an Amendment with more flexibility, removing this 50–50 basis altogether. The Committee is quite entitled to ask the Secretary of State for an explanation as to the meaning of the Amendment. What are the purposes of this Amendment? The Secretary of State seems to be getting to the position where the slightest question makes him rattled. The other night we had more than two-hours debate because the right hon. Gentleman did not give us a simple explanation of the meaning of the word "Executives." That was on the Electricity Reorganisation (Scotland) Bill, and that debate went on for 2½ hours because the right hon. Gentleman would not, or could not, explain what was in the Bill.
I have never know a Bill to go through this House without explanations being given as required. We are entitled to ask for explanations, so that we may understand what is in the Bill. Now the Secretary of State introduces an Amendment and explains to us that there is nothing sinister about it. I have accepted his word on that, but, evidently, he has not made inquiry as to the purpose of the Amendment. I can see good purposes in it and I can see other purposes in it. At least it makes Clause 5 fit in with the variability of Clause 4, which can go up and down, backwards and forwards, all round the circle, and nobody knows where it will end. On the other hand, Clause 5 was so definite and decided that it made Clause 4 irrational. Therefore, this Amendment makes Clause 5 harmonise with Clause 4.
But, Sir Rhys, it ought not to be for me to explain that to the Committee. It ought to be for the Secretary of State or the Lord Advocate. I do not know whether the Lord Advocate has studied this Bill at all. He never gives any explanations, he reiterates a phrase, and that is supposed to clear up something which it does not make clear, because the right hon. and learned Gentleman is not as lucid as we have a right to expect.
We on this side of the Committee are not lawyers. My hon. Friend has raised some legal points, but they have not been cleared up and we are entitled to know what Clauses mean. We have no intention of opposing this Amendment, but we are entitled to know what it means, what will be the effect on the local authorities, and the local authorities are entitled to know. So I put this direct question to the Secretary of State: If the local authorities can produce evidence to him that the 50–50 basis is not satisfactory, will this make it possible for him to consider that basis and, if necessary, bring in an order that alters the basis in accordance with his discussions with the local authorities?
The answer is simple: Yes, it will be possible.
Does the Secretary of State realise that he is holding himself and his Government up to the ridicule of the nation? First, he proposes this Amendment, then he adduces reasons to justify the Amendment which he hopes will satisfy the Committee, then, on being worsted in debate by the arguments adduced on this side of the Committee, the right hon. Gentleman says he will give an undertaking that there will be no legislation of this kind in this Parliament. Does he realise that he cannot give an undertaking for the next Parliament, that he cannot legislate for the next Parliament? Then, as a last resort, he changes once more and asks leave to withdraw the Amendment.
The Committee and the nation are entitled to know upon which of those three legs he stands because, like a Manxman, he seems to have three. First, the right hon. Gentleman proposes; then he gives an undertaking; then he asks leave to withdraw the 1783 Amendment. This is treating the Committee with disrespect. The Secretary of State is not entitled to do that. He was asked for an explanation in justification of the Amendment and then, with great pettiness, he said, "Very well, I will withdraw the Amendment." That is not the way to treat the Committee.
During my intervention I asked the Secretary of State at least six pointed questions. He replied to one of them and left the others unanswered. I shall repeat the one which concerns me vitally. Does the proposed Amendment to Clause 5 apply to Clause 4 (2, a)? As I understand the position it would apply technically. I am seriously perturbed at that and would gladly welcome the offer of the right hon. Gentleman to withdraw this Amendment, because it has far-reaching effects which I believe were never intended.


text:
Q: Prove convergence of the sequence $(z_1+z_2+\cdots + z_n)/n$ of Cesaro means Prove that if $\lim_{n \to \infty}z_{n}=A$ then:
 $$\lim_{n \to \infty}\frac{z_{1}+z_{2}+\cdots + z_{n}}{n}=A$$
I was thinking spliting it in: $$(z_{1}+z_{2}+\cdots+z_{N-1})+(z_{N}+z_{N+1}+\cdots+z_{n})$$
where $N$ is value of $n$ for which $|A-z_{n}|<\epsilon$
then taking the limit of this sum devided by $n$ , and noting that the second sum is as close as you wish to $nA$ while the first is as close as you wish to $0$. Not sure if this helps....

A: This can be an easy consequence of a more general statement which is from Polya's Problems and Theorems in Analysis:

Let $\{a_n\}_{n=1}^{\infty}$ be a real sequence such that $\lim_{n\to\infty}a_n=a$. And we have a family of finite sequences $\{\{b_{nm}\}_{m=1}^{m=n}\}_{n=1}^{\infty}$:
  $$
b_{11}\\
b_{21},b_{22}\\
b_{31},b_{32},b_{33}\\
\cdots
$$
  such that
  $$
b_{mn}\geq 0
$$
  for all $m,n$,
  and $\sum_{m}b_{nm}=1$ for each $n=1,2,\cdots$. Let $\{c_n\}_{n=1}^{\infty}$ be such that
  $$
c_n=\sum_{m=1}^na_mb_{nm}
$$
  Then $\lim_{n\to\infty}c_n=a$ if and only if $\lim_{n\to\infty}b_{nm}=0$ for each $m$.

The question in OP is a special case of the statement by letting
$$
b_{nm}=\frac{1}{n},\quad m=1,2,\cdots.
$$

A: It seems like Homework problem, hence I'll just give hint:
$$\frac{z_1+z_2+\cdots +z_n}{n}-A=\frac {(z_1-A)+(z_2-A)+\cdots +(z_n-A)}{n}$$
Now use the defn of limit that for every $\epsilon > 0$ there exists $N_0 \in \mathbb N$ such that $|z_m-A| < \epsilon \ \forall m \geq N_0$
Also remember triangle inequality : $|a_1+a_2+\cdots +a_n| \leq |a_1| + |a_2| +\cdots +|a_n|$
Can you find proper $a_i$ in terms of say $z_i$'s??

A: Let $\epsilon >0$
We have that  $\lim_{n \rightarrow \infty}z_n=A$ thus $\exists n_1 \in \mathbb{N}$ such that $|z_n-A|< \epsilon, \forall n \geqslant n_1$
$|\frac{z_1+...+z_n}{n}-A|=|\frac{(z_1-A)+...(z_{n_1-1}-A)}{n}+\frac{(z_{n_1}-A)+...+(z_n-A)}{n}| \leqslant \frac{|z_1-A|+...+|z_{n_1-1}-A|}{n}+ \frac{|z_{n_1}-A|+...+|z_n-A|}{n}$
Exists $n_2 \in \mathbb{N}$, by Archimedean property, such that $$\frac{|z_1-A|+...+|z_{n_1-1}-A|}{n}< \epsilon, \forall n \geqslant n_2$$
Now for $n \geqslant n_0= \max\{n_1,n_2\}$
$|\frac{z_1+...+z_n}{n}-A| \leqslant \epsilon+ \frac{(n-n_1) }{n}\epsilon<2 \epsilon $

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When planning your wedding, there are many things that you will learn from those around you. There are things that are nice to know and then there are things that you really need to know and will be glad that someone told you. If you are still wondering whether there is something you might have missed here are few tips to planning the perfect Indian wedding in Long Island.
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Home » PHARMACOKINETICS AND BIOEQUIVALENCE ASSESSMENT OF ORAL RIVAROXABAN TABLET IN IRANIAN HEALTHY VOLUNTEERS
PHARMACOKINETICS AND BIOEQUIVALENCE ASSESSMENT OF ORAL RIVAROXABAN TABLET IN IRANIAN HEALTHY VOLUNTEERS
Maryam Dibaei 1, Adel Haghighi 2, Ali Akbar Golabchifar 3, Kourosh Sadeghi 4, Nader Pourghasem 5, Abdollah Tavassoli 6 and Mohammad Reza Rouini * 1
Biopharmaceutics Division, Department of Pharmaceutics 1, Department of Clinical Pharmacy 4, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Department of Pathobiology, Science and Research Branch 2, Islamic Azad University, Tehran, Iran
Department of Pharmacology 3, Tehran University, Tehran, Iran.
Department of Study and Development 5, Veterinary Organization, Tehran, Iran.
Department of Analytical Chemistry 6, University of Mazandaran, Babolsar, Iran.
ABSTRACT: Rivaroxaban is utilized as a direct factor Xa inhibitor for the prevention and remedy of thromboembolic disorders. This study aimed to evaluate a generic version of rivaroxaban 10 mg tablet. Considering previous reports of safety and tolerability of a single dose (1.25-80 mg) of rivaroxaban, this study used a randomized, single-dose two-way crossover of rivaroxaban in 28 healthy volunteers, with a washout period of seven days. Analyses of blood samples were performed by a validated ultra-high performance liquid chromatography coupled with tandem mass spectrometry. An YMC-Pack ODS-AQ reversed-phase column with the mobile phase of acetonitrile and 10 mM ammonium acetate pH = 3 (70:30, v/v) at a flow rate of 0.3 mL.min-1 under isocratic elution was selected for the analysis. A range of 2.5-600 ng.mL-1 was obtained for the calibration curve. Pharmacokinetic parameters were calculated for the bioequivalence assessment. The results showed that two formulations have similar pharmacokinetics. The 90% confidence interval of the mean ratios of the test versus reference formulation of Ln transformed AUC0-30 (82.0-98.0), AUC0-inf (81.3-105.2), and Cmax (82.4-104.4) were within the acceptable range of 80-125%.
Bioequivalence, Pharmacokinetics, Rivaroxaban, Anticoagulant
INTRODUCTION: Two products containing the same drug are claiming to be bioequivalent when there is no significant difference in both the rate and extent of absorption of their active ingredient. Cmax (peak plasma concentration) and Tmax (Time to peak plasma concentration) indicate the rate of absorption, while AUC (area under the plasma concentration-time curve) reflects the extent of absorption 1.
For many decades, vitamin K antagonists (VKAs) have been the only oral anticoagulants. VKAs are administered orally and are effective in clinical uses, but their slow onset, interaction with food and drugs, and unpredictable outcomes in pharmacokinetics and pharmacodynamics present a limited therapeutic window.
Oral anticoagulants, which play a direct and particular role in only one coagulation factor, have been established in recent years. Rivaroxaban, Apixaban, and Dabigatran etexilate with predictable pharmacokinetics and pharmaco-dynamics are examples of direct oral anticoagulants for administration in specific thromboembolic disorders 2-6. Rivaroxaban Fig. 1 (5-chloro-N-({(5S)- 2- oxo- 3-[4-(3-oxo-4-morpholinyl)phenyl]-1, 3-oxazolidin-5-yl}methyl)- 2- thiophenecarboxa-mide) (C19H18ClN3O5S) is a direct Factor Xa (FXa) inhibitor in concentration-dependent procedures 7, 8. FXa plays a key role in thromboembolic disorders because it is the main site in which thrombin generation is reinforced. The size and chemical structure of rivaroxaban enable the drug to interact properly with FXa 7. Having a molecular weight of 435.88, and low-solubility, high-permeability features place rivaroxaban in the category of BCS Class II drugs 3. The first rivaroxaban oral tablet (Xarelto®), which indicated for the prevention and treatment of thromboembolic disorders does not require cofactors to apply its anticoagulant effect 3, 4.
Initial clinical studies have shown it to have a reasonable safety and tolerability profile in healthy subjects 7. The absolute bioavailability of a 10 mg dose of rivaroxaban, when given orally, is 80-100%. Fasting and fed condition do not influence the AUC or Cmax of a 10 mg tablet 3, 7-8. In contrast, under fasting conditions, the bioavailability of a 20 mg tablet was reduced by 66%. The biological half-life of rivaroxaban is 9 h in healthy subjects 9, 10.
In humans, rivaroxaban has shown high plasma protein binding (mainly binding to albumin), which results in low to moderate affinity to peripheral tissues. With low tissue penetration, rivaroxaban shows a distribution volume of approximately 50 L at steady state 3.
Rivaroxaban metabolites, which are eliminated via renal clearance and the hepatobiliary route, are produced by cytochrome P450 (CYP) and CYP-independent derived mechanisms. The residual, unchanged drug is eliminated in the urine 3, 7. Rivaroxaban is a substrate of P-glycoprotein (P-gp). While CYP3A4 and CYP2J2 metabolize rivaroxaban, it does not produce any active metabolite in circulation, and pre-systemic extraction does not reduce the high bioavailability of rivaroxaban. Previous studies revealed that co-administration of rivaroxaban with potent inhibitors of both CYP3A4 and P-gp cause a significant increase in rivaroxaban plasma concentrations 7. There is a correlation between dose and exposure of rivaroxaban. Increasing the dose administration of rivaroxaban (5-20 mg) causes a proportionate rise of rivaroxaban exposure 5.
This study aimed to compare the pharmacokinetics and bioavailability of a generic rivaroxaban tablet and the reference product in healthy Iranian volunteers.
FIG. 1: CHEMICAL STRUCTURE OF RIVAROXABAN
MATERIALS and METHODS:
Subjects: The protocol was approved by the Ethical Committee of Tehran University of Medical Science (IR.TUMS.TIPS.REC.1397.047), and all subjects signed the informed consent. Twenty-eight healthy male and non-pregnant, nonlactating female volunteers with normal medical examinations that consisted of laboratory tests (serum chemistry, hematology, urinalysis), medical history, and physical examination were enrolled in this study. Volunteers with an allergy to rivaroxaban or its excipients or with a history of acute or chronic disease were excluded from the study. No smokers were involved. There was the exclusion of volunteers with a medical history that would influence the final results.
Study Design: This study was performed at the Tehran University of Medical Sciences. This randomized study was designed as a single-dose, two-period, two-sequence crossover study to determine the bioequivalence of two formulations of rivaroxaban 10 mg in healthy Iranian adults. All subjects fasted for 10 h before and 3 h after dose administration. Additionally, subjects forbade to drink water from 1 h before to 1 h after drug administration. Two oral tablets (2 × 10 mg) of Axabin® (Arena Hayat Danesh Pharma Co, Tehran, Iran) or Xarelto® (Bayer Schering Pharma AG, Berlin, Germany) were randomly administered as the test and reference products, respectively, with 240 mL water for each subject in each period, with a washout of one week between two periods. Blood samples (2 mL) were collected through a peripheral vein at 0 (predose) and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 24, and 30 h after drug administration. Heparin saline was injected for prevention of blood clotting. Blood samples were immediately centrifuged, and plasma was frozen at –70 °C until drug analysis.
Drug Analysis: Stock solutions of rivaroxaban and carvedilol (internal standard) (1 mg.mL-1) were made in methanol. Plasma samples for calibration at concentrations of 2.5, 5, 10, 25, 50, 100, 150, 200, 300, and 600 ng.mL-1 were prepared by diluting rivaroxaban stock solution with blank plasma. The within-day and between-day accuracy and precision determinations and the recovery study were accomplished with three replicates of four different quality control QC samples.
Experiments were conducted using a Flexar ultra-high performance liquid chromatography (UHPLC) system (Perkin Elmer, Waltham, MA) consisting of a Flexar isocratic pump, Flexar LC autosampler, and a YMC-Pack ODS-AQ C18 (s-3 μm, 50 × 2.1 mm internal diameter [ID]) column compartment (YMC, Wilmington, NC) with a thermo stabilizer. The mass spectrometric analysis was performed using an API 3200 triple, a quadruple instrument from Applied Biosystems SCIEX (Foster City, CA, USA) equipped with a Turbo Ion Spray ionization source. An electrospray ionization (ESI) source operated in positive ion mode was applied in the mass spectrometer. Multiple reaction monitoring (MRM) of the analyte (m/z 436.1→144.9) and internal standard (m/z 407.1→99.1) were used for the making of calibration curve 11, 12.
The mobile phase consisted of acetonitrile, 10-mM ammonium acetate pH = 3 (70:30, v/v) and the flow rate was 0.3 mL.min-1. The column temperature was maintained at 30 °C. To 200 μL of plasma in an Eppendorf polypropylene tube, was added 500 μL internal standard solution (20 ng.mL-1 in methanol), vortexed for 1 minute, and centrifuged at 1500 g for 5 min. Ultimately, 5 μL of supernatant was injected into the UHPLC column. Each standard solution was analyzed 3 times, and the average ratio of peak drug area to internal standard was selected as an instrument response.
Pharmacokinetic Analysis: The pharmacokinetic parameters of two rivaroxaban formulations were determined by non-compartmental methods from the plasma drug concentration-time data by PK Solver 13. Cmax and Tmax were obtained directly from the individual plasma concentration-time curves. AUC0-t was calculated by utilization of the trapezoidal rule from time 0 to the time of the last measurable concentration. AUC0-inf was AUC0-t+Ct/Kel (kel was obtained from the slope of log-linear regression of the terminal phase of plasma drug concentration-time curves).
Statistical Analysis: Subjects in the first and second-period blood sampling were included in the statistical analysis. The values of Cmax, AUC0-t, AUC0-∞, and kel obtained from the two study periods were analyzed. For the evaluation of bioequivalence between test and reference drugs, the mean ratios of the test versus reference formulation of Ln transformed AUC0-t, AUC0-inf and Cmax were compared. This comparison was based on parametric 90% confidence intervals 14.
RESULTS: In two study periods, there was no serious adverse effect after the administration of 2 × 10 mg rivaroxaban tablets. This study was completed with 26 subjects in each period. The demographic data are summarized as follows: mean age, 35 y; mean body weight, 94 kg; and mean height, 174 cm. Two volunteers discontinued the study for personal reasons. The validation of the assay procedure was performed based on an assessment of several parameters. The linear range was observed over a concentration range of 2.5–600 ng.mL-1. The sensitivity of analysis was efficient enough for quantitative assay of this study. The limit of quantification (LOQ) of rivaroxaban in plasma samples, which had a relative standard deviation of less than 20%, was 2.5 ng.mL-1. The limit of detection (LOD) was 1 ng.mL-1. The range of within and between day precision and accuracy was 1.2-8.4% and 94.1-104.5%, respectively. The recovery was in the range of 94.4-99.2% Table 1.
The mean plasma concentration-time curves of rivaroxaban for test and reference formulations are shown in Fig. 2. The pharmacokinetics parameters of test and reference formulations are exhibited in Table 2. The median Cmax of the test and reference formulations were 268.0 and 304.0 ng.mL-1 and the median times to attain Cmax values were 2 and 2.5 h, respectively. The median AUC0–30 and AUC0–inf values were computed as 1953.0 and 2207.3 ng.hr.mL-1 for the test formulation and 2029.0 and 2513.1 ng.hr.mL-1 for the reference formulation.
TABLE 1: WITHIN AND BETWEEN DAY PRECISION AND ACCURACY AND RECOVERY OF DETERMINATION OF RIVAROXABAN IN HUMAN PLASMA
Plasma Conc.
(ng.mL-1) Within-day Between-day Recovery
RSD Accuracy RSD Accuracy % RSD
10 2.0 104.3 8.4 96.9 94.4 7.2
50 4.4 97.6 3.5 94.1 96.5 9.7
100 1.8 96.3 1.2 97.0 95.7 2.9
300 1.3 104.5 6.8 104.2 99.2 3.9
FIG. 2: MEAN PLASMA CONCENTRATION vs. TIME PROFILE OF RIVAROXABAN FOLLOWING ADMINISTRATION OF 2 × 10 mg TABLETS OF TEST AND REFERENCE FORMULATIONS TO 26 HEALTHY SUBJECTS. Error bars show a standard error for the mean.
The median calculated half-life of rivaroxaban was 9.3 and 10.2 h for the test and reference formulations, respectively. The 90% CIs and power of test and reference for Ln transformed ratios of pharmacokinetics parameters for bioequivalence evaluations are shown in Table 3.
The 90% confidence interval for the mean ratios of the test versus reference formulation of Ln transformed AUC0-30, AUC0-inf, and Cmax were 82.0-98.0, 81.3-105.2, and 82.4-104.4, respectively. Additionally, 90% confidence intervals for AUC0–t, AUC0–inf, and Cmax ratios were within allowable limits.
TABLE 2: SUMMARY OF AXABIN® AND XARELTO® PHARMACOKINETIC PARAMETERS
Parameters Test Product Median (Range) Reference Product Median (Range)
Cmax (ng.mL-1) 268.0 (159.0-550.0) 304.0 (157.0-691.0)
AUC0-30 (ng.hr.mL-1) 1953.0 (1064.7 -3970.7) 2029.0 (1070.5 -4691.7)
AUC0-inf (ng.hr.mL-1) 2207.3 (1096.1 -6396.0) 2513.1 (1296.0 -5491.7)
Tmax (h) 2.0(1-3) 2.5 (1-4)
T1/2 (h) 9.3 (4.5-29.7) 10.2 (6.8-20.9)
Cl/F (L.h-1) 9.1 (3.1-18.2) 8.0 (3.6-15.4)
TABLE 3: THE 90% CIS AND POWER OF TEST AND REFERENCE FOR LN TRANSFORMED PHARMACOKINETIC PARAMETERS Cmax, AUC0-30 AND AUC0-INF FOR RIVAROXABAN
Parameter AUC0-30 AUC0-inf Cmax
Lower 90% CI 82.0 81.3 82.4
Upper 90% CI 98.0 105.2 104.4
Power 0.99 0.98 0.99
DISCUSSION: Results from the previous phase I studies on single- and multiple-dose administrations of rivaroxaban indicated that the drug exhibited predictable pharmacokinetics and is therefore safe for the treatment of thromboembolic disorders. However, no pharmacokinetic and bioequivalence studies of rivaroxaban have been conducted in the Iranian population. In phase I studies of rivaroxaban in Japan, Germany and the US, the tolerability and safety of rivaroxaban has been reported up to 80 mg and 30 mg twice daily (for 5 days) in single and multiple doses, respectively 5. There was no identification of main safety issues on both treatments, where they were effectively endured.
This study was intended to evaluate the pharmacokinetics and bioequivalence of the 10 mg oral rivaroxaban tablet and a new generic form of the drug. This was a cross-over study that carried out bioequivalence testing between the Iranian brand-name and reference formulation of the drug rivaroxaban. The examined formulations were administered to 28 subjects.
The accurate determination of rivaroxaban was performed by a sensitive and specific UHPLC-tandem mass spectrometry, which has been applied in several clinical studies 15-17. According to obtained values regarding accuracy and precision, the assay method had repeatability within and between days, and the measurements constituted an acceptable closeness to the known values, respectively. A crossover design was applied to give both formulations to every subject, where this was done through separation by a 1-week washout period. This is more than five times the 5-9 h half-life identified in prior researches. Foreseeable pharmacokinetics has been seen for rivaroxaban in healthy subjects 3. The general pharmacokinetic profiles of rivaroxaban in test and reference formulations were similar. Calculation of the administration of every treatment and all pharmacokinetic parameters resulted in serial blood samples over 30 h. The PK parameters AUC0-t, AUC0-inf, and Cmax of rivaroxaban were the main endpoints. Standard non-compartmental methods from the plasma concentration-time data of rivaroxaban were used to estimate PK parameters. This was done after a single dose of test and reference treatments were administered. The Cmax for the test and reference formulations appeared similar to previously published pharmacokinetic studies 3.
In a study by Zhao et al., in Chinese subjects, following administration of oral doses of rivaroxaban 10, 20 mg, median Cmax were 143.2 and 204.4 μg.L-1, respectively 5. In another study in white male subjects, administration of 15 mg rivaroxaban showed median AUC and Cmax 1250 ng.h.mL-1 and 152.9 ng.mL-1, respectively 4. The highest level of inhibition of FXa activity is found within 1-4 h after a single-dose administration of rivaroxaban; 5 additionally, the independence of the pharmacokinetics and pharmacodynamics of rivaroxaban with age, weight, or gender have been displayed in other studies, which suggests that the administration of fixed dosing in patients is likely reasonable 7.
About FDA guidelines, confidence interval approaches are recommended for bioequivalence assessments. Based on the average Ln-transformed ratios of pharmacokinetics parameters, AUC0–30, AUC0–inf, and Cmax should fall within the allowable equivalence range (0.8-1.25).
CONCLUSION: In conclusion, the results of this study confirmed the bioequivalence of the generic rivaroxaban (Axabin®) and brand (Xarelto®) formulations in 26 healthy Iranian volunteers.
ACKNOWLEDGEMENT: We appreciate the Arena Hayat Danesh Pharma Co. for the financial support of this study.
CONFLICT OF INTEREST: The authors declared no conflict of interest.
US Food and Drug Administration. Guidance for industry bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA (2013). www.fda.gov/media/87219/download.
Kreutz R, Persson PB, Kubitza D, Thelen K, Heitmeier S, Schwers S, Becka M and Hemmrich M: Dissociation between the pharmacokinetics and pharmacodynamics of once‐daily rivaroxaban and twice‐daily apixaban: a randomized crossover study. Journal of Thrombosis and Haemostasis 2017; 15(10): 2017-28.
Mueck W, Stampfuss J, Kubitza D and Becka M: Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clinical Pharmacokinetics 2014; 53(1): 1-16.
Kubitza D, Becka M, Mueck W and Zuehlsdorf M: Rivaroxaban (BAY 59‐7939)–an oral, direct Factor Xa inhibitor–has no clinically relevant interaction with naproxen. British Journal of Clinical Pharmacology 2007; 63(4): 469-476.
Zhao X, Sun P, Zhou Y, Liu Y, Zhang H and Mueck W: Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects. British Journal of Clinical Pharmacology 2009; 68(1): 77-88.
Krause M, Henningsen A, Torge A, Juhl D, Junker R and Kenet G: Impact of gender on safety and efficacy of Rivaroxaban in adolescents & young adults with venous thromboembolism. Thrombosis Research 2016; 148: 145-151.
Kreutz R: Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundamental & Clinical Pharmacology 2012; 26(1): 27-32.
Zhang L, Peters G, Haskell L, Patel P, Nandy P and Moore KT: A cross‐study analysis is evaluating the effects of food on the pharmacokinetics of rivaroxaban in clinical studies. The Journal of Clinical Pharmacology 2017; 57(12): 1607-15.
Rivaroxaban APAR: Australian Public Assessment Report for Rivaroxaban. http://www.tga.gov.au/auspar/ auspar-rivaroxa, 2012.
Stampfuss J, Kubitza D, Becka M and Mueck W: The effect of food on the absorption and pharmacokinetics of rivaroxaban. International Journal of Clinical Pharmacology and Therapeutics 2013; 51(7): 549-561.
Magiera S: Fast, simultaneous quantification of three novel cardiac drugs in human urine by MEPS–UHPLC–MS/MS for therapeutic drug monitoring. Journal of Chromatography B 2013; 938: 86-95.
Derogis PB, Sanches LR, de Aranda VF, Colombini MP, Mangueira CL, Katz M, Faulhaber AC, Mendes CE, dos Santos Ferreira CE, França CN and de Campos Guerra JC: Determination of rivaroxaban in patient's plasma samples by anti-Xa chromogenic test associated to High Performance Liquid Chromatography-tandem Mass Spectrometry (HPLC-MS/MS). PloS one 2017; 12(2): e0171272.
Zhang Y, Huo M, Zhou J, Xie S and Solver PK: An add-in program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Computer Methods and Programs in Biomedicine 2010; 99(3): 306-314.
Bolton S and Bon C: Pharmaceutical statistics: practical and clinical applications. CRC Press, Fifth Edition 2009.
Lindahl S, Dyrkorn R, Spigset O and Hegstad S: Quantification of apixaban, dabigatran, edoxaban, and rivaroxaban in human serum by UHPLC-MS/MS-Method Development, Validation, and Application. Therapeutic Drug Monitoring 2018; 40(3): 369.
Schellings MW, Boonen K, Schmitz EM, Jonkers F, Van Den Heuvel DJ, Besselaar A, Hendriks JG and van de Kerkhof D: Determination of dabigatran and rivaroxaban by ultra-performance liquid chromatography-tandem mass spectrometry and coagulation assays after major orthopedic Thrombosis Research 2016; 139: 128-34.
Korostelev M, Bihan K, Ferreol L, Tissot N, Hulot JS, Funck-Brentano C and Zahr N: Simultaneous determination of rivaroxaban and dabigatran levels in human plasma by High-Performance Liquid Chromatography-tandem mass spectrometry. Journal of Pharmaceutical and Biomedical Analysis 2014; 100: 230-5.
Dibaei M, Haghighi A, Golabchifar AA, Sadeghi K, Pourghasem N, Tavassoli A and Rouini MR: Pharmacokinetics and bioequivalence assessment of oral rivaroxaban tablet in Iranian healthy volunteers. Int J Pharm Sci & Res 2019; 10(10): 4705-10. doi: 10.13040/IJPSR. 0975-8232.10(10).4705-10.
Authors: M. Dibaei, A. Haghighi, A. A. Golabchifar, K. Sadeghi, N. Pourghasem, A. Tavassoli and M. R. Rouini *
Authors Address: Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.
Email: rouini@tums.ac.ir
Revised: 07 March 2019
DOI: 10.13040/IJPSR.0975-8232.10(10).4705-10

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