Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment.
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, th...
| Publicado en: | European Journal of Clinical Pharmacology Vol. 70; no. 1; pp. 29 - 36 |
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| Autores principales: | , , , , , , , , |
| Formato: | research tables/charts Journal Article |
| Publicado: |
Springer Nature
Jan2014
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104130176&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104130176 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Jan2014 vid: 70 iid: 1 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 104130176 93392399 10.1007/s00228-013-1590-9 NLM24096683 PMC3889630 104130176 ppf: 29 ppct: 7 formats: fmt: @attributes: type: P tig: atl: Pharmacokinetics of dolutegravir in HIV-seronegative subjects with severe renal impairment. aug: au: Weller, Stephen Borland, Julie Chen, Shuguang Johnson, Mark Savina, Paul Wynne, Brian Wajima, Toshihiro Peppercorn, Amanda Piscitelli, Stephen affil: GlaxoSmithKline, Research Triangle Park, GlaxoSmithKline, 5 Moore Drive Research Triangle Park 27709 USA sug: subj: Antiviral Agents Administration and Dosage Antiviral Agents Pharmacokinetics HIV Seronegativity Kidney Diseases Complications Drugs, Investigational Anti-HIV Agents Human Descriptive Statistics Creatinine Antiviral Agents Blood Antiviral Agents Adverse Effects Male Female Adult Middle Age Aged Data Analysis Software Analysis of Covariance Confidence Intervals Adolescence Correlation Coefficient Funding Source Adult: 19-44 years Middle Aged: 45-64 years Aged: 65+ years Adolescent: 13-18 years Male Female ab: 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, matched subjects: 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. pubtype: Academic Journal doctype: research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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