Hepatic safety and tolerability in the maraviroc clinical development program.

Maraviroc is the first CCR5 antagonist to be approved for the treatment of HIV-1 infection. It is generally well tolerated, with a similar side-effect profile to placebo in controlled studies. Many agents used to treat HIV disease are associated with the potential for hepatotoxicity. The hepatic effects of maraviroc were analyzed across all Pfizer-sponsored maraviroc clinical trials, in which 2350 volunteers received maraviroc. Although sporadic hepatic enzyme abnormalities were reported in 34 phase 1/2a studies of up to 28-day duration, they demonstrated no dose relationship or association with hyperbilirubinemia. In the four phase 2b/3 studies in antiretroviral -naive and antiretroviral-experienced patients, there was no significant imbalance in hepatic enzyme abnormalities or hepatobiliary adverse events in maraviroc versus comparator arms up to week 96. The findings were similar in patients coinfected with hepatitis B and/or C virus, although the number of coinfected patients was small. No patient met the strict definition for Hy's Law. Two participants reported severe hepatotoxicity and although other potential causes were present, the contribution of maraviroc to these events could not be excluded. This analysis suggests that maraviroc does not present significant risks to hepatic safety when taken at the recommended doses in the populations studied.

Maraviroc for previously treated patients with R5 HIV-1 infection.

BACKGROUND: CC chemokine receptor 5 antagonists are a new class of antiretroviral agents. METHODS: We conducted two double-blind, placebo-controlled, phase 3 studies--Maraviroc versus Optimized Therapy in Viremic Antiretroviral Treatment-Experienced Patients (MOTIVATE) 1 and MOTIVATE 2--with patients who had R5 human immunodeficiency virus type 1 (HIV-1) only. They had been treated with or had resistance to three antiretroviral-drug classes and had HIV-1 RNA levels of more than 5000 copies per milliliter. The patients were randomly assigned to one of three antiretroviral regimens consisting of maraviroc once daily, maraviroc twice daily, or placebo, each of which included optimized background therapy (OBT) based on treatment history and drug-resistance testing. Safety and efficacy were assessed after 48 weeks. RESULTS: A total of 1049 patients received the randomly assigned study drug; the mean baseline HIV-1 RNA level was 72,400 copies per milliliter, and the median CD4 cell count was 169 per cubic millimeter. At 48 weeks, in both studies, the mean change in HIV-1 RNA from baseline was greater with maraviroc than with placebo: -1.66 and -1.82 log(10) copies per milliliter with the once-daily and twice-daily regimens, respectively, versus -0.80 with placebo in MOTIVATE 1, and -1.72 and -1.87 log(10) copies per milliliter, respectively, versus -0.76 with placebo in MOTIVATE 2. More patients receiving maraviroc once or twice daily had HIV-1 RNA levels of less than 50 copies per milliliter (42% and 47%, respectively, vs. 16% in the placebo group in MOTIVATE 1; 45% in both maraviroc groups vs. 18% in MOTIVATE 2; P<0.001 for both comparisons in each study). The change from baseline in CD4 counts was also greater with maraviroc once or twice daily than with placebo (increases of 113 and 122 per cubic millimeter, respectively, vs. 54 in MOTIVATE 1; increases of 122 and 128 per cubic millimeter, respectively, vs. 69 in MOTIVATE 2; P<0.001 for both comparisons in each study). Frequencies of adverse events were similar among the groups. CONCLUSIONS: Maraviroc, as compared with placebo, resulted in significantly greater suppression of HIV-1 and greater increases in CD4 cell counts at 48 weeks in previously treated patients with R5 HIV-1 who were receiving OBT. (ClinicalTrials.gov numbers, NCT00098306 and NCT00098722.)

Assessing theoretical risk and benefit suggested by genetic association studies of CCR5: experience in a drug development programme for maraviroc.

The proliferation of published gene association studies of the CCR5delta32 mutation is of relevance to drug development of a CCR5 antagonist for HIV, in highlighting potential safety concerns. We conducted an initial review of all non-HIV gene association studies of CCR5-delta32, followed by detailed meta-analyses in the three disease areas most commonly reported. Our review indicated no consistent evidence of increased risk of susceptibility to hepatitis C virus infection or multiple sclerosis among individuals with CCR5-delta32 mutation, and suggested treatment with a CCR5 inhibitor is unlikely to have related adverse effects. There was, however, evidence to suggest rheumatoid arthritis as a potential therapeutic target for a CCR5 antagonist. Clinical evidence would be required to confirm these findings.

Pharmacovigilance during the pre-approval phases: an evolving pharmaceutical industry model in response to ICH E2E, CIOMS VI, FDA and EMEA/CHMP risk-management guidelines.

Pharmacovigilance science has traditionally been a discipline focussed on the postmarketing or post-authorisation period, with due attention directed towards pre-clinical safety data, clinical trials and adverse events. As the biological sciences have evolved, pharmacovigilance has slowly shifted toward earlier, proactive consideration of risks and potential benefits of drugs in the pre- and peri-approval stages of drug development, leading to a maturing of drug safety risk management. Further advances in biology, pharmacology and improvements in computational applications to medicine have led to the development of more complex medicines previously unobtainable and have also permitted a more thorough assessment of risks and potential benefits even earlier in the development process. Elevated public concern with the safety of more sophisticated medicines, combined with new science, have led pharmaceutical innovators, regulators and healthcare professionals to collaborate to develop guidelines, which drive enhanced pharmacovigilance and safety risk management earlier in drug development. In this paper, we review international guidelines on pharmacovigilance planning applicable to the pre-approval phases of medicines development and provide author opinion on these guidelines' potential drug safety implications. We discuss the possible evolution of a pharmaceutical industry model to respond to these guidelines; a view on multidisciplinary safety management teams is provided to encourage refinement of safety-signal identification and risk assessment early in drug development and to communicate important safety concerns to internal research efforts, patients, investigators and regulators. We further describe these functions in the context of the complexities of vulnerable populations, including the example of medicines research for paediatric populations. We also discuss the special role of epidemiology in pre-approval drug development and the impact on epidemiological science of changes to the pharmacovigilance paradigm.