NCT00775294.

Aims-To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, Nacetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and compare this with data from uninfected, healthy volunteers.Methods-Ten HIV-infected men and seven women on medication affecting CYP enzyme activity were phenotyped four times over 2 months using caffeine, dextromethorphan, and midazolam. Urinary caffeine and dextromethorphan metabolite ratios were used to phenotype CYP1A2, NAT2, XO, and CYP2D6 activity and midazolam plasma clearance was used to phenotype CYP3A activity. Plasma and urine samples were analyzed by validated LC/UV or LC/MS methods for midazolam, caffeine, and dextromethorphan. Noncompartmental pharmacokinetics and nonparametric statistical analyses were performed, and the data compared with those of healthy volunteer historic controls.Results-Compared with age and sex-matched healthy volunteers, HIV-infected subjects had 18% lower hepatic CYP3A4 activity, 90% lower CYP2D6 activity, 53% lower NAT2 activity, and 22% higher XO activity. No significant difference was found in CYP1A2 activity. Additionally, 25% genotype-phenotype discordance in CYP2D6 activity was noted in HIV-infected subjects. Intraindividual variability in enzyme activity increased by 42-62% in HIV-infected patients for CYP1A2, NAT2, and XO, and decreased by 33% for CYP2D6. Interindividual variability in enzyme activity increased by 27-63% in HIV-infected subjects for CYP2D6, CYP1A2, and XO, and decreased by 38% for NAT2. Higher plasma TNFα concentrations correlated with lower CYP2D6 and CYP3A4 activity.Conclusions-Infection with HIV or stage of HIV infection may alter Phase I and II drug metabolizing enzyme activity. HIV infection was related to an increase in variability of these drugmetabolizing enzymes. Altered metabolism may be a consequence of immune activation and cytokine exposure.

More than 20 individual and fixed-dose combinations of antiretrovirals are approved for the treatment of human immunodeficiency virus (HIV) infection. However, owing to the ongoing limitations of drug resistance and adverse effects, new treatment options are still required. A number of promising new agents in existing or new drug classes are in development or have recently been approved by the US FDA. Since these agents will be used in combination with other new and existing antiretrovirals, understanding the potential for drug interactions between these compounds is critical to their appropriate use. This article summarizes the drug interaction potential of new and investigational protease inhibitors (darunavir), non-nucleoside reverse transcriptase inhibitors (etravirine and rilpivirine), chemokine receptor antagonists (maraviroc, vicriviroc and INCB 9471), integrase inhibitors (raltegravir and elvitegravir) and maturation inhibitors (bevirimat).Advances in the treatment of human immunodeficiency virus (HIV) infection include the discovery of new antiretroviral agents and an improved understanding of the optimal combination of these agents for therapeutic benefit. Currently, the most potent antiretroviral regimens are those that include a combination of medications targeting different stages of the HIV life cycle. In 2007, two new classes of antiretrovirals were approved by the US FDA, and a number of other novel antiretrovirals in new classes and existing classes are being developed. All of these drugs are promising options for treatment-experienced patients. However, each class has a unique drug-interaction profile, making the optimal combination of these drugs challenging. Encouragingly, some of these new agents are not substrates of either cytochrome P450 (CYP) enzymes or drug transport proteins. This increases their potential to be used in combination with currently available antiretroviral agents without concern for subtherapeutic or supratherapeutic exposures. This article reviews the drug-drug interaction data, as well as drug-drug interaction potential, for antiretrovirals that have recently become available or are currently undergoing later phase clinical study. New protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are featured, as are new agents in the chemokine receptor antagonist class, the integrase inhibitor class, and the maturation inhibitor class. A summary of interactions between antiretrovirals can be found in tables I-III, and a summary of interactions between these new antiretrovirals and concomitant medications is presented in table IV. DarunavirDarunavir is a new protease inhibitor recently approved for the treatment of HIV-1-infected patients. In the US, the approved dose of darunavir is 600 mg, administered in conjunction with 100 mg of ritonavir, every 12 hours with food. Darunavir is recommended for use in treatment-experienced (multiple protease inhibitor-resistant) adult patients (figure 1a).1.1.1 Pharmacology-The molecular weight of darun...

Background Antiretroviral therapy (ART) has become a central component of combination HIV prevention efforts. Defining the individual exposure of commercially available ART in genital secretions and vulnerable mucosal tissues is paramount to designing future prevention interventions. Methods A pharmacokinetic study was performed in 12 HIV-negative men receiving darunavir 600mg, ritonavir 100mg, and etravirine 200mg orally twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on Day 1 (PK1) and Days 7 and 8 (PK2). One rectal tissue (RT)sample from each subject was collected during PK1 and PK2. During PK1, two seminal plasma (SP)samples were collected from each subject. During PK2, six SP samples were collected from each subject over 2 days. Results Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80–92% (DRV), 89–95% (RTV), 83–88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. RT AUCs were higher than BP by 39 to 155-fold for darunavir, 12 to 61-fold for ritonavir, and 20 to 40-fold for etravirine. Conclusions Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared to BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir+ritonavir and etravirine in secondary prevention.

Aim Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians. Materials & methods CYP450 2B6, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects. Results Allele frequencies (variant) were: CYP2B6 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*1B (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP2B6 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27–2.40) for area under the concentration time curve (AUC)0–12 h, 1.58 (1.03–2.42) for C0, and 0.53 (0.31–0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP2B6 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027). Conclusion Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP2B6 516 was significantly associated with nevirapine exposure.