Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK‐453,061), in healthy adult subjects

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Lersivirine (UK-453,061) is predominantly cleared by glucuronidation (UGT2B7) and oxidation via cytochrome P450 (CYP) 3A4.• Lersivirine metabolism, and thus pharmacokinetics, may be affected by concomitant administration of drugs affecting CYP3A4 and UGT2B7.• Ketoconazole is a potent inhibitor of CYP3A4 and an inhibitor of UGT2B7. Valproic acid is a potent inhibitor of UGT2B7. WHAT THIS STUDY ADDS• Combined inhibition of CYP3A4 and UGT2B7 with ketoconazole increases the exposure of lersivirine, and may warrant lersivirine dose adjustment to compensate for this interaction.• Inhibition of UGT2B7 with valproic acid does not have a substantial effect on lersivirine pharmacokinetics. AIMSTo investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK-453,061), a next generation non-nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co-administration of lersivirine with these inhibitors. METHODSTwo open-label, randomized, placebo-controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400 mg once daily) on the pharmacokinetics of lersivirine (250 mg once daily). Subjects received ketoconazole 400 mg once daily or placebo on days 1-2 and received lersivirine 250 mg once daily and ketoconazole 400 mg once daily or placebo on days 3-9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000 mg once daily) on the PK of lersivirine (500 mg once daily). On days 1-7, subjects received lersivirine 500 mg once daily plus either VPA 1000 mg or placebo. RESULTSCompared with lersivirine alone, co-administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24 h)) and maximum plasma concentration (Cmax) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24 h) by 25% (90% CI 16%, 35%), with little effect on Cmax (2.5%, 90% CI -9%, 16%). There were no serious adverse events and no treatment-related discontinuations from either study. CONCLUSIONSInhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7-mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co-administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated.

Independent Predictors of Delay in Emergence From General Anesthesia

“…10,25,26 Because propofol is metabolized by CYP2C9 and UGT1A9, 27 it was expected that valproic acid would be an independent predictor of delayed emergence. On the other hand, clobazam is a weak inducer of CYP3A4 and has the potential to induce UGT1A1, but it does not have a significant induction or inhibition effect on CYPs at clinically meaningful concentrations in vitro.…”

Target Enzyme‐Activated Two‐Photon Fluorescent Probes: A Case Study of CYP3A4 Using a Two‐Dimensional Design Strategy

“…Hence, NEN could be used to screen and characterize the CYP3A4 modulators.U nlike general CYP3A4-detecting assays such as the previous probebased assays or antibody-based enzyme-linked immunosorbent assays, NEN provides as imple and rapid approach to selectively detect CYP3A4 activity in cells or crude proteomes in real-time. [23] When pretreated with 1and 10 mm indinavir, the fluorescence signal decreased to 37.1 %a nd 16.8 %ofthe control, implying the dose-dependent inhibitory effect of indinavir toward CYP3A4 ( Figure S17). [21] In our study,zebrafish larvae display aclear and strong fluorescence region, which corresponded precisely to the liver region of the zebrafish ( Figure 5A-a-c).…”

“…Meanwhile,t here was nearly no effect of the known nonmodulators of CYP3A4. [23] When pretreated with 1and 10 mm indinavir, the fluorescence signal decreased to 37.1 %a nd 16.8 %ofthe control, implying the dose-dependent inhibitory effect of indinavir toward CYP3A4 ( Figure S17). Similarly, the phenomenon was observed in the TKZ-and nilotinibtreated group.T herefore, NEN could monitor changes in CYP3A4 and faithfully reported the drug-induced inhibition of CYP3A4 in living zebrafish.…”

The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part II: Pharmacological issues and further understanding

“…Other articles describe VPA as an inhibitor of UGT2B7, 84,85 UGT2B15 and UGT1A9. 84 In summary, the author is not absolutely sure which UGTs may be inhibited by VPA; the literature provides a complicated and sometimes contradictory picture.…”