Article

Pharmacokinetics of enfuvirtide in pediatric human immunodeficiency virus 1-infected patients receiving combination therapy.

Roche, Nutley, NJ 07110, USA.
The Pediatric Infectious Disease Journal (Impact Factor: 3.14). 01/2005; 23(12):1137-41.
Source: PubMed

ABSTRACT Enfuvirtide is the first of a new class of antiretroviral agents, the fusion inhibitors.
The primary objective of this analysis was to evaluate the pharmacokinetics of 2.0 mg/kg enfuvirtide in human immunodeficiency virus 1 (HIV-1)-infected children and adolescents when administered in combination with at least 3 other antiretrovirals.
Twenty-five HIV-1-infected pediatric patients (5-16 years of age) enrolled in an ongoing phase I/II study were included in this analysis. Patients received enfuvirtide 2.0 mg/kg sc twice daily (bid) for at least 7 days. Blood samples were collected on day 7, and plasma concentrations of enfuvirtide and its metabolite were measured by a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetics measures [Cmax, tmax, Ctrough, and area under the concentration time curve time 0 to 12 hours (AUC12 hours)] were calculated from plasma concentration-time data by standard noncompartmental methods.
There was no significant difference between children and adolescents for enfuvirtide Cmax (6.43 versus 5.88 microg/mL), Ctrough (2.87 versus 2.98 microg/mL) and AUC12 hours (56.1 versus 52.7 hours . microg/mL). Similarly no significant differences were found when the pharmacokinetic measures were compared based on sexual maturity stages. A post hoc regression analysis based on AUC12 hours showed that body weight-adjusted dosing of enfuvirtide provides drug exposure that is independent of age group, body weight and body surface area.
Body weight-adjusted dosing of enfuvirtide, at a dose of 2.0 mg/kg sc bid, in HIV-1-infected pediatric patients at least 5 years of age, provides drug exposure comparable with that previously observed in HIV-1-infected adults after 90 mg sc bid dosing. Drug exposure in children and adolescents is independent of age group, body weight, body surface area and sexual maturity stage.

0 Followers
 · 
75 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: There are over 2.1 million HIV-infected children worldwide, who are increasingly exposed to antiretroviral therapy. Given the enormous physiological changes associated with maturation, the role of individualized therapy and optimal dosing in children and adolescents is likely different than in adults. This review summarizes the pharmacodynamics, pharmacokinetics and pharmacogenomics of antiretroviral therapy in children and adolescents, and it discusses the roles of these in the optimization of therapy through the practice of therapeutic drug monitoring/management. Within the pharmacodynamics section are tables and discussion about what is known of the relationships between drug concentrations, inhibitory quotients and effects - both desired and toxic. The pharmacokinetics section summarizes all reported antiretroviral pharmacokinetic data in children, divided into data from population and non-population analytic approaches. Measures of interindividual pharmacokinetic variability are reported. Sampling strategies for the measurement and the interpretation of plasma antiretroviral drug concentrations are suggested, as well as dosing with degrees of renal or hepatic failure. Relevant pharmacogenomic polymorphisms are summarized, and the role for pharmacogenomics testing is discussed. Incorporation of dose adjustment on the basis of measured serum drug concentrations is reviewed, including all such paediatric experience reported in the literature. Discussion of the influences of malnutrition and herbal remedies is also included. Finally, consideration is given to future work in this field.
    Clinical Pharmacokinetics 03/2011; 50(3):143-89. DOI:10.2165/11539260-000000000-00000 · 5.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In resourced settings with access to highly active antiretroviral therapy, perinatally acquired HIV-1 infection has become a chronic disease of childhood with increasing numbers of adolescents surviving to adulthood and transitioning from pediatric to adult services. Advances in antiretroviral therapy, reductions in side effects, new classes and new drugs within existing antiretroviral classes offer enormous benefits, although issues around adherence during adolescence persist. The longer term impact of exposure to HIV and antiretroviral therapy throughout childhood are becoming apparent, with growing concern over neurocognitive, cardiovascular, renal and bone health. Careful follow-up of this early perinatal cohort as they enter adulthood will inform the future management of the growing numbers of adolescents surviving worldwide as access to therapy increases.
    Expert Review of Anticancer Therapy 12/2010; 8(12):1403-16. DOI:10.1586/eri.10.129 · 3.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The objective of this study was to characterize the population pharmacokinetics of enfuvirtide in HIV-1-infected children and adolescents. HIV-infected patients received combination antiretroviral therapy, including enfuvirtide 2.0 mg/kg subcutaneously, twice daily. Serial and trough blood samples were collected up to 48 weeks. NONMEM was used for population pharmacokinetic analysis. Enfuvirtide exposure was calculated from individual parameter estimates derived from the final model. A total of 218 samples from 43 patients were included in the analysis. Enfuvirtide plasma concentration-time data were described by a 1-compartment model with first-order absorption and elimination. The addition of each subject's actual body weight as a covariate affected CL/F but not V/F or K(a). The population CL/F, V/F, and K(a) for a 33-kg reference patient was 1.31 L/h, 2.31 L, and 0.105 h(-1), respectively. The final model was CL/F (L/h) = 1.31 . (body weight/33 [kg])(0.721). Age did not affect enfuvirtide exposure. These results confirm the appropriateness of body weight-based pediatric enfuvirtide dosing.
    The Journal of Clinical Pharmacology 04/2007; 47(4):510-7. DOI:10.1177/0091270006299089 · 2.47 Impact Factor