CYP3A5 genotype impacts maraviroc concentrations in healthy volunteers.
Drug Metab Dispos
; 42(11): 1796-802, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25117426
ABSTRACT
CYP3A5 plays a prominent role in the metabolism of maraviroc, an approved drug for human immunodeficiency virus (HIV)-1 treatment and a candidate for HIV-1 prevention. We studied the effect of the CYP3A5 genotype on pharmacokinetics of maraviroc and a primary CYP3A5-dependent metabolite of maraviroc denoted as metabolite 1 (M1). Volunteers were screened for health status and CYP3A5 genotype (wild-type allele *1 and dysfunctional alleles *2, *3, *6, and *7) to obtain 24 evaluable subjects in three groups (n = 8 each) homozygous dysfunctional (two dysfunctional alleles), heterozygous (one *1 allele and one dysfunctional allele), and homozygous wild-type (two *1 alleles). Subjects received 300 mg maraviroc orally followed by blood collection for 32 hours. The homozygous wild-type group exhibited lower mean plasma maraviroc concentrations at almost all sampling times. The median (interquartile range) maraviroc area under the plasma concentration-time curves from time 0 to infinity (AUC0-inf) were 2099 (1422-2568) ngâ
h/ml, 1761 (931-2640) ngâ
h/ml, and 1238 (1065-1407) ngâ
h/ml for the homozygous dysfunctional, heterozygous, and homozygous wild-type groups, respectively. The homozygous wild-type group had 41% lower maraviroc AUC0-inf and 66% higher apparent clearance compared with the homozygous dysfunctional group (P = 0.02). The AUC0-inf ratios of maraviroc to M1 in heterozygous and homozygous wild-type subjects were lower by 51 and 64% relative to the homozygous dysfunctional group, respectively (P < 0.001). In conclusion, the lower maraviroc concentrations in the homozygous wild-type group indicate that maraviroc may be underdosed in people homozygous for the CYP3A5*1 allele, including almost one-half of African Americans.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Triazóis
/
Cicloexanos
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Inibidores da Fusão de HIV
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Citocromo P-450 CYP3A
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Voluntários Saudáveis
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
/
Adult
/
Aged
/
Humans
/
Middle aged
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article