 |
|
|
| |
A pilot study evaluating plasma and intracellular pharmacokinetics (PK) of switching from atazanavir (ATV) 400mg QD to ATV 200 mg BID in HIV+ patients
|
| |
| |
Reported by Jules Levin
9th International Workshop on Clinical Pharmacology of HIV Therapy
April 7-9, 2008
New Orleans
S. Bonora1, A. D'Avolio1, C. Tettoni1, M. Siccardi1, D. Gonzalez de Requena1, L. Baietto1, C. Cometto1, M. Sciandra1, L. Trentini1, G. Di Perri1
1University of Torino, Infectious Diseases, Torino, Italy
Program Abstract
Background: Plasma exposure to ATV in recipients of unboosted ATV 400 mg QD may be suboptimal in a measurable proportion of cases. Administration of unboosted ATV as 200 mg bid might result in more appropriate exposure. Moreover, no data on intracellular accumulation of unboosted ATV have been yet obtained in the clinical setting. Therefore, we performed a pilot plasmatic and intracellular PK study of switching from ATV 400 mg QD to ATV 200 mg BID.
Material & Methods: Ten immuno-virologically stable HIV+ patients administered with an ATV 400 mg QD-containing HAART gave informed consent to switch ATV to 200 mg BID for 10 days. On day 0 and 10 they underwent to repeated sampling over the dosing interval and plasma and intracellular (PBMCs-associated) ATV concentrations were measured by an HPLC-UV and HPLC-MS validated methods, respectively. Total bilirubin levels corresponding to Ctrough24 and Ctrough12 were measured. Non-compartmental pharmacokinetic parameters were calculated and expressed as geometric mean, GM (CI 95%). Concentrations were expressed as ng/ml or ng/ml.h (AUC).
Results: GM plasma Ctrough, Cmax and AUC24h for ATV 400 QD were 138 (58-220), 2786 (1780-3792), and 20780 (14364-27196), respectively. GM ratios 200BID-to-400QD for plasmatic Ctrough, Cmax and AUC24h were calculated to be 2.19 (1,21-3,17), 0.48 (0,24-0,72) and 0.80 (0,47-1,13), respectively. GM values of total bilirubin plasma levels corresponding to Ctrough24h (ATV 400 mg QD) and Ctrough12h (ATV 200 mg BID) were 1,35 (0,74-1,96) and 1,78 (1,16-2,4) mg/dl, respectively. GMs of intracellular Ctrough, Cmax and AUC24h for ATV 400 QD were 465 (253-678), 4058 (2698-5420), and 35958 (22534-49382), respectively. GM ratios PBMC-to-plasma concentrations were calculated to be 2,93 (1,49-4,42), 1,27 (0,17-2,37), 1,51 (0,5-2,52) for Ctrough, Cmax and AUC24h, respectively. GM ratios 200BID-to-400QD for intracellular Ctrough, Cmax and AUC24h resulted to be 1,86 (0,95-2,75), 0.53 (0,07-0,99) and 0.90 (0,02-1,78), respectively.
Conclusion: Administration of ATV 200 mg BID resulted in optimisation of plasma exposure (higher Ctrough, lower Cmax and substantially equivalent AUC) as compared to standard 400 mg QD. Increase of Ctrough led to a potentially advantage in terms of efficacy, being 50% of patients patients on ATV 400 mg QD as compared to 20% of subjects on ATV 200 mg BID below the suggested ATV minimum effective concentration (150 ng/ml). Concomitant increase of bilirubin levels, known to be correlated with ATV Ctrough, was not clinically significant. ATV administered at 400 mg QD showed to accumulate within the cells to a slightly greater extent than in the plasma, being its penetration higher at Ctrough point measurement, although with a marked inter-individual variability. After switching to ATV 200 mg BID, magnitude of changes of intracellular exposure were similar to those observed in plasma. In conclusion, switch to ATV 200 mg BID dosing warrants further clinical evaluation in selected patients.
|
| |
|
|
|
|
|
