Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment.
Eur J Clin Pharmacol
; 70(1): 29-35, 2014 Jan.
Article
en En
| MEDLINE
| ID: mdl-24096683
ABSTRACT
PURPOSE:
Dolutegravir (DTG), an unboosted HIV integrase inhibitor (INI), is metabolized by UGT1A1 and to a minor extent by CYP3A. Renal elimination of unchanged DTG is very low (< 1 %). As renal impairment may affect pharmacokinetics (PK), even for drugs primarily metabolized or secreted in bile, this study investigated the effect of renal impairment on the PK of DTG.METHODS:
This was an open-label, single-dose study of oral DTG 50 mg administered to subjects with severe renal impairment (creatinine clearance [CLcr] <30 mL/min; not on dialysis) and to healthy controls (CLcr >90 mL/min) matched for gender, age and body mass index (8 subjects per group). Serial PK samples were collected up to 72 h post-dose for determination of DTG and DTG-glucuronide (DTG-Gluc) concentrations in plasma. DTG unbound fraction in plasma was determined at 3 and 24 h. PK parameters were determined by non-compartmental methods and compared between groups by analysis of covariance.RESULTS:
DTG was well tolerated with a low incidence of Grade 1 adverse events. DTG PK parameters showed significant overlap between groups. DTG mean exposure was lower in subjects with severe renal impairment compared to healthy, matchedsubjects:
AUC(0-∞) and Cmax were 40 % and 23 % lower, while mean DTG-Gluc was increased. Renal impairment did not affect DTG fraction unbound in plasma.CONCLUSIONS:
The modest reductions in mean PK exposures for DTG and increases for DTG-Gluc in the severe renal impairment group are not considered clinically significant. DTG does not require dose adjustment in patients with renal impairment.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Inhibidores de Integrasa VIH
/
Insuficiencia Renal
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Compuestos Heterocíclicos con 3 Anillos
Tipo de estudio:
Clinical_trials
Límite:
Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Eur J Clin Pharmacol
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos