Current guidelines recommend the use of at least two, and preferably three, fully active antiretroviral agents in an optimized regimen for the treatment of HIV infection in treatment-experienced patients (13,21). Therefore, it is important to study and understand drug-drug interactions between different antiretrovirals, because these can impact individual pharmacokinetic profiles and lead to suboptimal responses and/or increased toxicities (5).Maraviroc is the first in a novel class of entry inhibitors, the chemokine C-C motif receptor 5 (CCR5) antagonists, and has demonstrated benefits for both treatment-naïve and treatment-experienced patients infected with CCR5-tropic HIV (11,14). Darunavir, in combination with low-dose ritonavir (darunavir-ritonavir), is an HIV protease inhibitor (PI) with demonstrated benefits for both treatment-naïve and treatment-experienced patients (10,17,19). Etravirine is an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI) with a high genetic barrier to the development of resistance, in contrast to the NNRTIs efavirenz and nevirapine, and shows potent activity against NNRTI-resistant viruses. The efficacy and safety of etravirine for treatment-experienced patients were demonstrated in the phase III DUET trials (15,16,18).Since maraviroc is a substrate of cytochrome P450 3A (CYP3A) and P-glycoprotein (6), and since darunavir-ritonavir and etravirine inhibit and induce CYP3A, respectively, and both inhibit P-glycoprotein (8,20), there is a likelihood of drug-drug interactions between these agents. For example, most HIV PIs (either with or without low-dose ritonavir) increase maraviroc exposure, necessitating a reduction of the maraviroc dose to 150 mg twice daily (b.i.d.) (6).This article reports the results from two separate drug-drug interaction studies with healthy volunteers: (i) the effect of darunavir-ritonavir on the pharmacokinetics of maraviroc, and vice versa (darunavir-ritonavir study), and (ii) the effect of etravirine, alone or in combination with darunavir-ritonavir, on the pharmacokinetics of maraviroc, and vice versa (etravirine study).The primary objectives of the studies were to investigate the effect of darunavir-ritonavir at 600 and 100 mg b.i. was the highest dose being studied in phase III studies at the time and was therefore selected for coadministration with etravirine alone; 150 mg of maraviroc b.i.d. was selected for coadministration with etravirine-darunavir-ritonavir based on the results of the darunavir-ritonavir study (2). The results should provide appropriate dose recommendations for maraviroc when it is coadministered with these drugs in clinical practice.
During elvitegravir/r plus maraviroc administration, no elvitegravir or ritonavir dose change and a reduced 150-mg dose of maraviroc are recommended.
ABSTRACT:The recently discovered selective nonsteroidal progesterone receptor (PR) antagonist 4-[3-cyclopropyl-1-(methylsulfonylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy-2,6-dimethylbenzonitrile (PF-02413873) was characterized in metabolism studies in vitro, in preclinical pharmacokinetics in rat and dog, and in an initial pharmacokinetic study in human volunteers. Clearance (CL) of PF-02413873 was found to be high in rat (84 ml ⅐ min ؊1 ⅐ kg ؊1) and low in dog (3.8 ml ⅐ min ؊1 ⅐ kg ؊1), consistent with metabolic stability determined in liver microsomes and hepatocytes in these species. In human, CL was low in relation to hepatic blood flow, consistent with metabolic stability in human in vitro systems, where identified metabolites suggested predominant cytochrome P450 (P450)-catalyzed oxidative metabolism. Prediction of CL using intrinsic CL determined in human liver microsomes (HLM), recombinant human P450 enzymes, and single species scaling (SSS) from pharmacokinetic studies showed that dog SSS and HLM scaling provided the closest estimates of CL of PF-02413873 in human. These CL estimates were combined with a physiologically based pharmacokinetic (PBPK) model to predict pharmacokinetic profiles after oral suspension administration of PF-02413873 in fasted and fed states in human. Predicted plasma concentration versus time profiles were found to be similar to those observed in human over the PF-02413873 dose range 50 to 500 mg and captured the enhanced exposure in fed subjects. This case study of a novel nonsteroidal PR antagonist underlines the utility of PBPK modeling techniques in guiding prediction confidence and design of early clinical trials of novel chemical agents.
The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.
There is considerable ongoing investment in the research and development of selective progesterone receptor (PR) modulators for the treatment of gynecological conditions such as endometriosis. Here, we provide the first report on the clinical evaluation of a nonsteroidal progesterone receptor antagonist 4-[3-cyclopropyl-1-(mesylmethyl)-5-methyl-1H-pyrazol-4-yl]oxy,-2,6-dimethylbenzonitrile (PF-02413873) in healthy female subjects. In in vitro assays, PF-02413873 behaved as a selective and fully competitive PR antagonist, blocking progesterone binding and PR nuclear translocation. The pharmacological mode of action of PF-02413873 seems to differ from the founding member of the class of steroidal PR antagonists, 11-4-dimethylaminophenyl-17-hydroxy-17␣-propinyl-4,9-estradiene-3-one (RU-486; mifepristone). Exposure-effect data from studies in the cynomolgus macaque, however, demonstrated that PF-02413873 reduced endometrial functionalis thickness to a comparable degree to RU-486 and this effect was accompanied by a decrease in proliferation rate (as measured by bromodeoxyuridine incorporation) for both RU-486 and high-dose PF-02413873. These data were used to underwrite a clinical assessment of PF-02413873 in a randomized, double-blinded, third-party open, placebo-controlled, dose-escalation study in healthy female volunteers with dosing for 14 days. PF-02413873 blocked the follicular phase increase in endometrial thickness, the midcycle lutenizing hormone surge, and elevation in estradiol in a dose-dependent fashion compared with placebo. This is the first report of translational efficacy data with a nonsteroidal PR antagonist in cynomolgus macaque and human subjects.
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