Medical Advocates for Social Justice
Conference Abstract

5th International Congress on Drug Therapy in HIV Infection
Glasgow, Scotland, October 22-26, 2000

Pharmacokinetic Interaction Between Lopinavir/Ritonavir (ABT-378/r) and Other Non-HIV Drugs

R BERTZ, A HSU, W LAM, L WILLIAMS, C RENZ, M KAROL, S DUTTA, R CARR, Y ZHANG, Q WANG, S SCHWEITZER, C FOIT, A ANDRE, B BERNSTEIN, GR GRANNEMAN AND E SUN


 

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ABT-378/r is a novel HIV protease inhibitor with mean trough concentrations that exceed its protein binding corrected EC50 for wild type HIV by > 75-fold when dosed at 400/100 mg BID. Liver microsome studies show ABT-378/r is a substrate and an inhibitor of CYP3A in vitro. Inhibition of other CYP isoforms in vitro, including CYP2D6, does not occur at clinically relevant concentrations. ABT-378/r is also a metabolic inducer. The purpose was to quantify in vivo pharmacokinetic interactions between ABT-378/r and non-HIV drugs that may be co-administered.

Several interaction studies were conducted with multiple-dose ABT-378/r 400/100 mg BID in healthy subjects (18-55 years). Index drugs included substrates, inhibitors and inducers of CYP3A. Studies were conducted using a sequential design, with at least 10 days (d) dosing of ABT-378/r in at least 12 subjects with the following drugs before and after ABT-378/r: methadone 5 mg single dose (SD), ketoconazole 200 mg SD, rifabutin 300 or 150 mg QD (10 d), ethinyl estradiol 35 m g/norethindrone 1 mg QD (7 d), atorvastatin 20 mg QD (4 d) or pravastatin 20 mg QD (4 d). Subjects also received 10 d of ABT-378/r before and after rifampin 600 mg QD (10 d), rifabutin 150 mg QD (10 d), or a 200 mg ketoconazole SD.

Point estimates of effect on AUC central values with 90% confidence intervals (CI):

Drug

AUC Ratio
(90% CI)

Drug

AUC Ratio
(90% CI)

Methadone

0.47 (0.42, 0.53)

Atorvastatin

5.88 (4.69, 7.37)

Ethinyl Estradiol

0.58 (0.54, 0.62)

Pravastatin

1.33 (0.91, 1.94)

Norethindrone

0.83 (0.73, 0.94)

Rifabutin

3.03 (2.79, 3.30)

Ketoconazole

3.04 (2.44, 3.79)

Rifabutin on ABT-378

1.17 (1.04, 1.31)

Ketoconazole on ABT-378

0.87 (0.75, 1.00)

Rifampin on ABT-378

0.25 (0.21, 0.29)

In vivo, ABT-378/r inhibits CYP3A-mediated clearance of ketoconazole, atorvastatin and rifabutin, and is a metabolic inducer of methadone and ethinyl estradiol. ABT-378 is susceptible to induction by rifampin, but not by rifabutin. ABT-378 is not susceptible to CYP3A inhibition by ketoconazole.

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Pharmacokinetic Interaction Between Lopinavir/Ritonavir (ABT-378/r) and Other Non-HIV Drugs

© 2000 Medical Advocates for Social Justice