Pharmacokinetics, Safety and Efficacy of Maraviroc in Treatment-experienced Pediatric Patients Infected With CCR5-Tropic HIV-1

Abstract

Background: Maraviroc is a CC-chemokine receptor 5 antagonist approved to treat adults infected with CC-chemokine receptor 5-tropic (R5) HIV-1. Study A4001031 was conducted to evaluate the pharmacokinetics, safety and efficacy of maraviroc in combination with optimized background therapy in treatment-experienced pediatric patients infected with R5 HIV-1 and support registration of maraviroc for pediatric use.

Methods: This is an open-label, 2-stage, age-stratified, noncomparative multicenter study. One-hundred and three participants were enrolled into 4 age/formulation cohorts and dosed twice daily. Initial doses were determined by body surface area and optimized background therapy, based on drug interactions with maraviroc in adults. Dose adjustment and pharmacokinetic reevaluation occurred if the average concentrations (Cavg) at Week 2 were <100 ng/mL (Stage 1-dose finding).

Results: Data from the Week 48 analysis demonstrated that 49/50 Stage 1 participants rolling over into Stage 2 (safety and efficacy) achieved Cavg ≥100 ng/mL. Doses were identified that achieved similar concentration ranges to those seen in adults. The majority (90/103) received optimized background therapy containing potent cytochrome P450 3A inhibitors. Maraviroc was well tolerated and the safety and efficacy were comparable to those of adults. All cohorts had a mean decrease from baseline in HIV-1 RNA of >1 log10. Increases from baseline in the median CD4+ cell count and percentage were seen for all age groups.

Conclusions: The maraviroc dosing strategy resulted in participants achieving the target Cavg, with exposure ranges similar to those observed in adults on approved doses. The safety and efficacy of maraviroc in this pediatric population were comparable to those seen in adults.

FIGURE 1.

Design of study A4001031. S1, Stage 1: Intensive PK/dose finding (4–12 weeks): Minimum of 12 (Cohort 1) and 10 children (in each of Cohorts 2–4) to complete Stage 1 before entering Stage 2. S2, Stage 2: Safety/Efficacy: Following the minimum numbers being reached for Stage 1, all new patients then directly entered Stage 2.

FIGURE 2.

Maraviroc plasma concentration vs. time (A) at Week 2 by cohort; (B–D) by interaction category compared with adult data. A: Median Week 2 concentrations for Stage 1 participants enrolled in Stage 2 (N = 50; participants on final dose). B: Patients receiving maraviroc with potent CYP3A inhibitors. Data from pediatric patients (N = 85) were compared with data from adult patients (N = 125) receiving maraviroc at the approved dose of 150 mg BID in combination with lopinavir/ritonavir, darunavir/ritonavir or atazanavir/ritonavir in Studies A4001027, A4001028 (MOTIVATE 1 and 2), A4001029 and A4001098. C: Patients receiving maraviroc with neutral agents. Data from pediatric patients (N = 10) were compared with data from adult patients (N = 402) receiving maraviroc at the approved dose of 300 mg BID in combination with neutral agents in studies A4001026 (MERIT), A4001027, A4001028 (MOTIVATE 1 and 2), A4001029 and A4001098. D: Patients receiving maraviroc with potent CYP3A inducers. Data from pediatric patients (N = 2) were compared with data from adult patients (N = 27) receiving maraviroc at the approved dose of 600 mg BID in combination with efavirenz or etravirine in study A4001098.^aCohort 1: ≥2 to <6 years of age, maraviroc oral solution.^bCohort 2: ≥6 to <12 years of age, maraviroc tablet formulation.^cCohort 3: ≥6 to <12 years of age, maraviroc oral solution.^dCohort 4: ≥12 to <18 years of age, maraviroc tablet formulation. BID indicates twice daily; LOWESS, locally weighted scatter plot smoothing.