Amprenavir (APV) and Lopinavir (LPV) Pharmacokinetics (PK) in

1
Paul A. Pham 1830 E. Monument Street Room 444
Baltimore, MD 21287Phone [phone]Email
vpham_at_jhmi.edu
Poster A-381 ICAAC 2006 San Francisco, CA
Amprenavir (APV) and Lopinavir (LPV)
Pharmacokinetics (PK) in HIV-infected Patients
Switched from APV 750 mg BID LPV/Ritonavir
(RTV) 533mg/133mg BID to Fosamprenavir (FPV) 1400
mg BID LPV/r 533mg/133mg BID P. Pham1, P.
Barditch-Crovo1, M. Parish1, C. Radebaugh1, E.
Fuchs1, K. Carson1, G. Pakes2, C.
Flexner1 1Department of Medicine, Johns Hopkins
University School of Medicine, Baltimore,
Maryland, 2GSK, RTP, NC
BACKGROUND Co-administration of APV or its
prodrug, FPV, with LPV/RTV leads to CYP3A4
induction and this, in turn, decreases the plasma
concentrations and exposure of each agent.
Despite this interaction, favorable virologic
outcomes have been described in patients
receiving regimens that combine APV with LPV/r.
However, due to the market withdrawal of APV 150
mg capsules, it is not known if the switch to FPV
will result adequate drug concentration and
virologic suppression.

• Pharmacokinetic and Statistical Analysis
• Pharmacokinetic analysis of plasma APV and LPV
  concentration-time data was conducted using
  noncompartmental methods with WinNonLin version
  4.1 (Pharsight Corporation, Mountain View, CA,
  USA).
• Summary statistics for each of the
  pharmacokinetic parameters of APV and LPV were
  tabulated by regimen.
• Paired t-test was used for pair-wise comparison
  of log-transformed PK parameters of APV and LPV.
• Point estimates and 90 confidence intervals of
  the geometric mean ratio (GMR) of PK parameters
  for APV and LPV were calculated.

APV PK Parameters
  APV 750mg BID LPV/r 533/133 mg BID (Regimen I) GM (95 CI) FPV 1400 mg BID LPV/r 533/133 mg BID (Regimen II) GM (95 CI) Regimen II vs I GM Ratio (90 CI)
Cmax, ng/mL 3499.87 (2650.60 4621.24) 6140.83 (5123.16 - 7360.66) 1.75 (1.42 2.17) P 0.001
Cmin, ng/mL 825.78 (588.34 1159.07) 1303.02 (921.19 1843.13) 1.58 (1.39 1.79) P lt 0.0001
AUCtau, ng?h/mL 19409 (13894 27113) 34237 (27188 43115) 1.76 (1.50 2.08) P 0.0001
RATIONALE To better understand the mixed effects
of enzyme induction and inhibition of FPV, LPV,
and RTV /- EFV combination after switching from
APV, we conducted an open-label pharmacokinetic
study at steady state.
RESULTS
LPV PK Parameters
Switching from APV 750 mg BID LPV/r 533mg/133mg
BID to FPV 1400 mg BID LPV/r 533mg/133mg BID
resulted in steady-state APV Cmax, Cmin and
AUCtau significantly increasing (by 75, 58,
and 76, respectively) and comparable LPV PK
parameters.
  APV 750mg LPV/r 533/133 mg BID (Regimen I) GM (95 CI) FPV 1400 mg LPV/r 533/133 mg BID (Regimen II) GM (95 CI) Regimen II vs I GMR (90CI)
Cmax, ng/mL 9657.74 (7560.25 12337.14) 9397.05 (6963.70 12680.69) 0.97 (0.81 - 1.17) P 0.80
Cmin, ng/mL 4330.28 (2823.39 6641.43) 3992.46 (2624.48 6073.48) 0.92 (0.79 1.07) P 0.35
AUCtau, ng?h/mL 78010 (58861 103389) 69811 (54180 89952) 0.89 (0.78 1.03) P 0.17

• OBJECTIVES
• Primary Objectives
• To compare the steady-state exposure of APV when
  given as APV 750 mg BID concomitantly with LPV/r
  533/133 mg BID, relative to the exposure of FPV
  1400 mg BID with LPV/r 533/133 mg BID.
• Secondary Objectives
• To describe the safety and tolerability of both
  combination regimens.
• To describe the short-term (12 weeks) efficacy in
  patients switched from APV 750 mg BID to FPV 1400
  mg BID when co-administered with LPV/r 533/133 mg
  BID.

RTV PK Parameters
Mean APV protein-binding (90) adj IC50 for
Multiple PI-resistant HIV (900ng/mL)
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  APV 750mg LPV/r 533/133 mg BID (Regimen I) GM (95 CI) FPV 1400 mg LPV/r 533/133 mg BID (Regimen II) GM (95 CI) Regimen II vs I GMR (90CI)
Cmax, ng/mL 802.15 (533.87 - 1205.24) 859.69 (484.85 1524.35) 1.07 (0.79 1.46) P 0.69
Cmin, ng/mL 174.57 (110.16 276.64) 137.13 (76.80 244.84) 0.79 (0.61 1.01) P 0.11
AUCtau, ng?h/mL 4838.26 (3235.93 7234.03) 4459.39 (2699.84 7365.68) 0.92 (0.75 1.13) P 0.49
METHODS In an open-label study, we investigated
steady-state APV, LPV, and RTV PK, short-term
efficacy, and tolerability after APV 750 mg BID
LPV/RTV 533mg/133mg BID (regimen 1 Reg 1) or
FPV 1400 mg BID LPV/RTV 533mg/133mg BID
(regimen 2 Reg 2 in 10 HIV-infected pts. Eight
pts stabilized (VLlt400 c/mL for 2 consecutive VL
readings 30 d apart) for 14 d on Reg 1 were
switched to Reg 2 and 2 pts stabilized on Reg 2
were switched to Reg 1. All background
medications remained unchanged. At
baseline and at Day 14 of each regimen, APV and
LPV maximum concentrations (Cmax), minimum
concentrations (Cmin), and area under the plasma
concentration-time curve (AUC) were assessed.
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Mean APV protein-binding (90) adj IC50 for
Wild-type HIV (146ng/mL)
Sale M et al Antimicrob Agents Chemother
200246746-754.
Regimen 1 APV 750 mg BID LPV/RTV 533/133mg BID 8 pts w/ VLlt400 c/mL 2 pts w/ VLlt400 c/mL Regimen 2 FPV 1400 mg BID LPV/RTV 533/133mg BID

• SAFETY
• Ten pts entered and completed the study
• All regimens were well tolerated.
• At 12 wks post-study, 7 (88) of the 8 pts
  switched from APV to FPV maintained a VL lt400
  c/mL and 1 was lost to f/u.
• Only 1 pt who switched from APV to FPV reported a
  grade 1 toxicity (loose stool)

Median LPV protein-binding (90) adj IC50 for
Multiple PI-resistant HIV (3080ng/mL 8-10
mutations)
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• CONCLUSION
• Switching from a regimen of APV 750 mg BID
  LPV/r 533mg/133mg BID to FPV 1400 mg BID LPV/r
  533mg/133mg BID resulted in steady-state APV
  Cmax, Cmin and AUCtau increasing by 75, 58, and
  76, respectively, comparable LPV and RTV PK
  parameters, and no change in tolerability.

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Mean LPV protein-binding (90) adj IC50 for
Wild-type HIV (70ng/mL)
Kempf DF et al J Virol 2001757462-7469. Kapla
n SS and Hicks CB Expert Opin Pharmacother
200561573-1585.
The authors would like to thank our volunteers,
nurses, GCRC grant RR-00052, and GlaxoSmithKline
for research grant support.