Some of these drugs also induce the enzyme UGT1A1 and thus reduce blood plasma concentrations of cabotegravir, further compromising the effectiveness of this combination therapy.It is also contraindicated in combination with proton pump inhibitors because the increased gastric pH causes decreased rilpivirine absorption from the gut, with similar consequences as with CYP3A4 inducers. Adverse effects
The most common side effects of the injectable formulation are reactions at the injection site (in up to 84% of patients) such as pain and swelling, as well as headache (up to 12%) and fever or feeling hot (in 10%). Less common (under 10%) are depressive disorders, insomnia, and rashes. The most common side effects of the tablets are also depressive disorders (4.1%), headache (3.5%), insomnia (3.5%) and rashes (2.3%). All of these side effects occurred under combination therapies of rilpivirine with one or more other drugs against HIV. QT prolongation of the heart rhythm has been observed at very high doses, but is not clinically relevant at standard doses of the drug. Pharmacology
Mechanism of action
Rilpivirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI). Pharmacokinetics
When taken by mouth, rilpivirine reaches highest levels in the blood plasma after about four to five hours. Taking the drug without food lowers its plasma levels by 40% as compared to taking it with food, which is considered to be clinically relevant. Therefore, patients are advised to take the medication together with a meal.
Levoketoconazole, sold under the brand name Recorlev, is a steroidogenesis inhibitor that is used for the treatment of Cushings syndrome. Levoketoconazole was approved for medical use in the United States in December 2021.Levoketoconazole is the levorotatory or (2S,4R) enantiomer of ketoconazole, and it is an inhibitor of the enzymes CYP11B1 (11β-hydroxylase), CYP17A1 (17α-hydroxylase/17,20-lyase), and CYP21A2 (21-hydroxylase). It inhibits glucocorticoid biosynthesis and hence circulating levels of glucocorticoids, thereby treating Cushings syndrome. In addition to its increased potency, the drug is 12-fold less potent than racemic ketoconazole in inhibiting CYP7A1 (cholesterol 7α-hydroxylase), theoretically resulting in further reduced interference with bile acid production and metabolite elimination and therefore less risk of hepatotoxicity. Levoketoconazole has also been found to inhibit CYP11A1 (cholesterol side-chain cleavage enzyme) and CYP51A1 (lanosterol-14α-demethylase), similarly but more potently relative to ketoconazole. References
External links
"Levoketoconazole". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03277690 for "A Study to Assess the Safety and Efficacy of Levoketoconazole in the Treatment of Endogenous Cushings Syndrome" at ClinicalTrials.gov
Clinical trial number NCT01838551 for "Treatment for Endogenous Cushings Syndrome (SONICS)" at ClinicalTrials.gov