title: Pharmacokinetics, safety, and tolerability of maraviroc in HIV-negative subjects with impaired renal function.
abstract: OBJECTIVE
  This open-label, nonrandomized, parallel-group study was conducted to explore the pharmacokinetics, safety, and tolerability of maraviroc in renally impaired subjects.
  
  
  METHODS
  Subjects with normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease (ESRD) (n = 6 per group) were enrolled. Subjects with normal function (period 1), severe impairment, and ESRD received a single 300 mg dose of maraviroc. Subjects with normal function (period 2), mild impairment, and moderate impairment received 150 mg for 7 days at adjusted intervals of twice daily, once daily, and every 48 hours, respectively, with saquinavir/ritonavir (SQV/r). Maraviroc was quantified in plasma, urine, and dialysate by tandem high-performance liquid chromatography-mass spectrometry.
  
  
  RESULTS
  With SQV/r, geometric mean steady-state maraviroc area under the plasma concentration-time curve for the dosing interval (AUCtau) was 5,341 (coefficient of variation [CV], 27%), 8,119 (35%), and 6,193 (27%) h•ng/mL, in normal function, mild, and moderate impairment groups, respectively. Without SQV/r, 2% to 3% of the maraviroc dose was recovered in urine versus 15% to 25% of steady-state dose when given with SQV/r. Moderate to high intersubject variability in exposure was noted. AUC from zero to infinity (AUCinf) was similar to historical single-dose data in subjects with ESRD: low in those with normal function, and high in those with severe impairment. Dialysis did not influence maraviroc exposure. Maraviroc was well tolerated.
  
  
  CONCLUSIONS
  The data suggest that no dosing interval adjustments are required in subjects with renal impairment when maraviroc is administered alone. However, maraviroc dosing interval adjustment is warranted in renally impaired patients receiving potent CYP3A4 inhibitors. Reference to local prescribing information is recommended, because dose recommendations in renally impaired patients may differ between regions.
authors.affiliation: Pfizer Global Research and Development, New York, New York 10017, USA. manoli.vourvahis@pfizer.com
authors.forename: Manoli
authors.initials: M
authors.lastname: Vourvahis
authors.forename: Juanzhi
authors.initials: J
authors.lastname: Fang
authors.forename: Tina
authors.initials: T
authors.lastname: Checchio
authors.forename: Ashley
authors.initials: A
authors.lastname: Milton
authors.forename: Barry
authors.initials: B
authors.lastname: Weatherley
authors.forename: Lynn
authors.initials: L
authors.lastname: McFadyen
authors.forename: Jayvant
authors.initials: J
authors.lastname: Heera
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D016022:Case-Control Studies; D003510:Cyclohexanes / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D005260:Female; D005786:Gene Expression Regulation; D006207:Half-Life; D006801:Humans; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000628:therapy; D008297:Male; D000077592:Maraviroc; D008875:Middle Aged; D006435:Renal Dialysis; D051437:Renal Insufficiency / Q000378:metabolism*; D012720:Severity of Illness Index; D014230:Triazoles / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D003510:Cyclohexanes; D065692:Cytochrome P-450 CYP3A Inhibitors; D014230:Triazoles; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D000077592:Maraviroc