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Pharmacokinetics of amprenavir given once or twice a day when combined with atazanavir in heavily pre-treated HIV-positive patients
  AIDS: Volume 17(18) 5 December 2003 pp 2669-2671
Guffanti, Monicaa; De Pascalis, Cleta Raffaellab; Seminari, Ea; Fusetti, Giulianaa; Gianotti, Nicolaa; Bassetti, Danteb; Galli, Andreaa; Castagna, Antonellaa; Lazzarin, Adrianoa
aDepartment of Infectious Diseases, Vita/Salute University, San Raffaele Scientific Institute, Milan, Italy; and bClinic of Infectious Diseases, University of Genoa c/o San Martino Hospital, Genoa, Italy.
We studied the pharmacokinetics of amprenavir at doses of 600 mg twice a day or 1200 mg once a day, when co-administered to HIV-positive patients with 400 mg a day of atazanavir without a ritonavir booster. Our preliminary results suggest that amprenavir and atazanavir could be co-administered and that amprenavir could be boosted by atazanavir without the need for ritonavir pharmaco-enhancement.
The strategy of combining two protease inhibitors (PI), with or without additional pharmaco-enhancement by low-dose ritonavir, can be used to increase antiretroviral efficacy in patients who have failed multiple lines of antiretroviral treatment. However, PIs may interact pharmacokinetically and, therefore, it is important to establish whether their standard doses should be modified when they are administered concomitantly. Amprenavir is preferentially administered to PI-experienced patients in combination with ritonavir as a pharmaco-enhancer. The two most widely used amprenavir/ritonavir dose regimens are 600/100 twice a day and 1200/200 every day.
Atazanavir is an investigational PI that has been shown to be a potent inhibitor of saquinavir metabolism, and will soon be available on the market.
The aim of this study was to examine the pharmacokinetic parameters of amprenavir administered once or twice a day when co-administered to HIV-positive patients with atazanavir without ritonavir pharmaco-enhancement.
Heavily pretreated HIV-positive patients included in the Atazanavir Expanded Access Program were studied as outpatients at the Clinic of Infectious Diseases,San Raffaele Hospital, Milan, Italy. Four were treated with amprenavir 600 mg twice a day in combination with atazanavir 400 mg a day (group A), and threewere treated with amprenavir 1200 mg a day plus atazanavir 400 mg a day (group B). Amprenavir and atazanavir were administered simultaneously in the morning.
All the patients received a nucleoside reverse transcriptase inhibitor backbone (group A: tenofovir in one patient, tenofovir and stavudine in one, lamivudineand stavudine in one, didanosine in one; group B: tenofovir in all), excluding any non-nucleoside reverse transcriptase inhibitors or other drugs potentially capable of interfering with the cythchrome P450 enzymatic system. Adherence to the drug intake was assessed using a questionnaire.
Serial blood samples for steady-state amprenavir analysis were collected after one or more week of concomitant treatment as follows: before the morningadministration, and then 1, 2, 3 and 8 h post-dosing in group A; the sampling times in group B were the same plus an additional sample at 24 h. Plasmaamprenavir concentrations were determined using a validated high- pressure liquid chromatography assay with a lower limit of quantification of 0.1 μg/ml.
Systemic amprenavir exposure (concentration just before the next dose, Ctrough; maximum plasma concentration, Cmax; and area under the plasmaconcentration-time curve from time 0 to 12 h, AUC0-12 in group A; Ctrough, Cmax and area under the plasma concentration-time curve from time 0 to 24 h,AUC0-24 in group B) was measured using non-compartmental methods.
The pharmacokinetic parameters of atazanavir were not evaluated in this study.
All seven patients had been heavily exposed to antiretroviral treatment, and were switched to atazanavir in combination with amprenavir as salvage therapy.The two groups were comparable in terms of sex (one woman and three men in group A, three men in group B), and median age (range) 40 (38-50) and 49(36-55) years. The median (range) CD4 cell count was 124 (86-260) cells/μl in group A and 210 (29-264) cells/μl in group B, the median plasma HIV-RNAlevel was respectively 41 800 (910-438 195) and 10 938 (1807-37 697) copies/ml.
At the time of the pharmacokinetic analysis, no side-effects of grade 3 or more had been recorded. The plasma amprenavir concentrations in the two groups are summarized in Table 1.
  Ctrough, Concentration just before the next dose.Group A: amprenavir 600 mg twice a day; group B: ampamprenavir 1200 mg a day.
The median (range) amprenavir Ctrough values were 1.49 (0.72-2.45) ug/ml in group A and 0.32 (0.26-0.85) ug/ml in group B, and the median amprenavirCmax values were 4.83 (6.59-12.26) and 12.26 (7.27-16.6) ug/ml, respectively. Peak plasma levels were reached between the first and the second hour in bothgroups.
The AUC0-12 was 51.3 (31.1-54.5) ug.h/ml in group A, and the AUC0-24 was 93.9 (61.4-128.7) ug.h/ml in group B.
The results of this pilot study suggest that amprenavir concentrations are substantially increased by the concomitant administration of atazanavir. Theconcentrations of amprenavir after the administration of 600 mg twice a day are comparable with, or perhaps even higher, than those found in patients receiving amprenavir 600 mg twice a day combined with ritonavir 100 mg twice a day. In a previous study, the amprenavir Ctrough, Cmax and AUC values reported as geometric means in patients receiving amprenavir/ritonavir (600/100) twice a day were 1.32 ug/ml, 5.59 ug/ml and 27.3 ug.h/ml, respectively. In another study, the corresponding figures were 1.92 ug/ml, 7.12 ug/ml and 35.74 ug.h/ml.
We found that the administration of amprenavir 1200 mg a day led to a higher Cmax and AUC, and a slightly lower Ctrough, in comparison with historicalcontrols.
Given their potential clinical relevance, our preliminary results need to be confirmed by a study involving a larger number of patients.
The possibility of combining atazanavir and amprenavir without ritonavir pharmaco-enhancement could be interesting, particularly because it would avoid the lipid abnormalities frequently observed during the course of treatments requiring ritonavir boosting. However, confirmation of this possibility would require the collection of atazanavir pharmacokinetic data.
If it were to be confirmed, the opportunity of being able to offer once-daily administration (currently used in the case of other PI combinations such asamprenavir/ritonavir and saquinavir/ritonavir) could increase patient compliance with treatment.
A further improvement in terms of reducing the pill burden could perhaps be gained by means of the once-daily administration of atazanavir and theamprenavir pro-drug GW908.
In conclusion, our results suggest that the co-administration of atazanavir 400 mg a day with both amprenavir 600 mg twice a day and amprenavir 1200 mg a day yield therapeutic levels of amprenavir in HIV-infected patients.
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