Interactions between amprenavir and the lopinavir-ritonavir combination in heavily pretreated patients infected with human immunodeficiency virus.
OBJECTIVE
This pharmacokinetic study was designed to characterize interactions between amprenavir and the lopinavir-ritonavir combination in patients infected with human immunodeficiency virus in whom previous antiretroviral therapy had failed.


METHODS
Twenty-seven patients included in a randomized clinical trial (ANRS [National Agency for AIDS Research] Protocol 104) participated in this study. They were randomized to receive ritonavir at a dose of either 100 mg twice daily or 200 mg twice daily. For the first 2 weeks of therapy, they were randomly assigned to receive lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily), amprenavir (600 mg twice daily) plus ritonavir (100 mg twice daily), lopinavir (400 mg twice daily) and ritonavir (100 mg twice daily) plus additional ritonavir (100 mg twice daily), or amprenavir (600 mg twice daily) plus ritonavir (200 mg twice daily). From week 3 onward, all patients received amprenavir plus lopinavir-ritonavir with or without an additional ritonavir dose (100 mg twice daily). The pharmacokinetics of the 3 drugs was studied in weeks 2 and 6 of therapy.


RESULTS
Median amprenavir concentrations decreased by 54% (P =.004) when lopinavir was added to the amprenavir-ritonavir regimen. Lopinavir weakly displaced amprenavir from plasma proteins: The average unbound fraction of amprenavir was 0.089 in week 2 and 0.114 in week 6 (P =.03), but this did not fully account for the observed interaction. Increasing the ritonavir dose did not affect the amprenavir concentration. The relationship between lopinavir and ritonavir concentrations fitted a maximum effect (E(max)) model;the average concentration of ritonavir that yielded a lopinavir concentration of 8119 ng/mL (50% of E(max)) was 602 ng/mL (coefficient of variation, 22%). There was a significant relationship between the lopinavir inhibitory quotient and the virologic response in week 2 (P =.005).


CONCLUSIONS
Lopinavir markedly decreases the amprenavir concentration during amprenavir and lopinavir-ritonavir combination therapy. The inhibitory quotients were more predictive of the short-term virologic response than was the level of drug exposure.
Taburet
Anne-Marie
AM
Clinical Pharmacy Department, Hôspitaux de Paris, Kremlin Bicêtre, Paris France. anne-marie.taburet@bct.ap-hop-paris.fr
Raguin
Gilles
G
Le Tiec
Clotilde
C
Droz
Cécile
C
Barrail
Aurélie
A
Vincent
Isabelle
I
Morand-Joubert
Laurence
L
Chêne
Geneviève
G
Clavel
François
F
Girard
Pierre-Marie
PM
D000284:Administration, Oral; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D001682:Biological Availability; D002219:Carbamates; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005663:Furans; D015658:HIV Infections / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D061466:Lopinavir; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011336:Probability; D011744:Pyrimidinones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018570:Risk Assessment; D019438:Ritonavir / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016879:Salvage Therapy; D012720:Severity of Illness Index; D016037:Single-Blind Method; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D015996:Survival Rate; D016896:Treatment Outcome; D019562:Viral Load
D002219:Carbamates; D005663:Furans; D011744:Pyrimidinones; D013449:Sulfonamides; D061466:Lopinavir; C095108:amprenavir; D019438:Ritonavir