Publications by authors named "Reshma Saskia Autar"

4 Publications

  • Page 1 of 1

Population pharmacokinetics of ritonavir-boosted saquinavir regimens in HIV-infected individuals.

J Antimicrob Chemother 2008 Dec 29;62(6):1344-55. Epub 2008 Sep 29.

NIHR National Biomedical Research Centre, Royal Liverpool and Broadgreen University Hospital Trust, Liverpool, UK.

Objectives: The aim of this study was to develop and validate a population pharmacokinetic model in order to describe ritonavir-boosted saquinavir concentrations dosed twice and once daily in human immunodeficiency virus (HIV)-infected patients from the UK, Uganda and Thailand and to identify factors that may influence saquinavir pharmacokinetics.

Methods: Pharmacokinetic data from 10 clinical studies were combined. Non-linear mixed effects modelling (NONMEM version V) was applied to determine the saquinavir pharmacokinetic parameters, interindividual/interoccasion variability (IIV/IOV) and residual error. Various covariates potentially related to saquinavir pharmacokinetics were explored, and the final model was validated by means of 95% prediction interval and testing the predictive performance of the model with data not included in the model-building process.

Results: Ninety-seven patients were included from the UK (n = 52), Uganda (n = 18) and Thailand (n = 27), contributing 347 saquinavir profiles (1-14 profiles per patient). A one-compartment model with zero-order absorption and lag-time best described the data with IIV/IOV on apparent oral clearance (CL/F) and volume of distribution (V/F) and with IIV on duration and absorption lag-time. The ritonavir area under the curve over the dosing interval was significantly associated with saquinavir CL/F and V/F. A typical patient from the UK had approximately 1.5- and 3-fold higher saquinavir CL/F compared with patients from Uganda (89.0 versus 49.8 L/h) and Thailand (89.0 versus 26.7 L/h), respectively.

Conclusions: A model to characterize ritonavir-boosted saquinavir pharmacokinetics in HIV-infected adults has been developed and validated. The model could be used for dosage adaptation following therapeutic drug monitoring and to assess patients' suitability for once-daily boosted saquinavir therapy.
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December 2008

Pharmacokinetics and short-term efficacy of a double-boosted protease inhibitor regimen in treatment-naive HIV-1-infected adults.

J Antimicrob Chemother 2008 May 18;61(5):1145-53. Epub 2008 Feb 18.

HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross AIDS Research Center Bangkok, 104 Ratchadamri Road, Pathumwan, Bangkok 10330, Thailand.

Objectives: To study the pharmacokinetics and short-term efficacy of low and standard dose lopinavir/ritonavir and saquinavir combinations in Thai, human immunodeficiency virus (HIV)-infected, treatment-naive patients.

Methods: In this open-label, 24-week, prospective study, 48 treatment-naive patients were randomized to lopinavir/ritonavir 400/100 mg+saquinavir 1000 mg twice daily (arm A), lopinavir/ritonavir 400/100 mg+saquinavir 600 mg twice daily (arm B), lopinavir/ritonavir 266/66 mg+saquinavir 1000 mg twice daily (arm C), or lopinavir/ritonavir 266/66 mg+saquinavir 600 mg twice daily (arm D). A 12 h. pharmacokinetic profile in all patients was performed. Plasma concentrations of saquinavir and lopinavir were determined using an HPLC technique. HIV-1 RNA was measured over 24 weeks.

Results: Forty-three subjects were included in the pharmacokinetic analysis. The total exposure differed significantly for the different arms. Median values for lopinavir area under the curve at 0-12 h were 128.2, 119.2, 66.1 and 68.5 mg.h/L for arms A-D, respectively. For saquinavir, the median values were 36.9, 19.2, 25.3 and 12.4 mg.h/L for arms A-D, respectively. The proportion of patients having a viral load below 50 copies/mL at week 24 was 39% for arm A, 63% for arm B, 55.0% for arm C, and 69% for arm D.

Conclusions: The pharmacokinetic parameters for the different treatment arms were adequate. However, the proportion of subjects with an undectable viral load at week 24 was lower than anticipated.
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May 2008

Ketoconazole is inferior to ritonavir as an alternative booster for saquinavir in a once daily regimen in Thai HIV-1 infected patients.

AIDS 2007 Jul;21(12):1535-9

HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), Thai Red Cross Aids Research Centre (TRCARC), 104 Rajdumri Road, 10330 Pathumwan, Bangkok, Thailand.

Objective: To improve the pharmacokinetics of protease inhibitors, boosting with low-dose ritonavir is performed. However, toxicity, storage conditions and high costs of antiretroviral treatment may necessitate interruption of ritonavir. Ketoconazole was investigated as a potential booster of once-daily (o.d.) saquinavir.

Methods: In a single-group, two-period design, 25 virologically and immunologically stable patients on saquinavir/ritonavir 2000/100 mg o.d. were switched to saquinavir/ketoconazole 2000/400 mg o.d. for 2 weeks. Two steady-state pharmacokinetic curves were recorded at both periods.

Results: Fourteen females and 11 male patients were included. Median age was 34 years [interquartile range (IQR), 32-42 years], body weight 54 kg (IQR, 47-59 kg) and body mass index 21 kg/m (19-23 kg/m). The mean saquinavir area under the curve (AUC) during boosting with ritonavir was 57.93 +/- 27.96 mg/h/l, maximum observed concentration (Cmax) was 7.50 +/- 3.45 mg/l and concentration at 24 h (Cmin) was 0.35 +/- 0.30 mg/l. When ketoconazole was used, the saquinavir AUC, Cmax, and Cmin were 12.00 +/- 6.97 mg/h/l, 2.43 +/- 1.35 mg/l and 0.03 +/- 0.04 mg/l, respectively.

Conclusion: Boosting with ketoconazole resulted in 80% lower exposure to saquinavir. Although saquinavir AUC might still be adequate for treatment, concentrations at 24 h reached levels below the recommended trough concentrations of 0.1 mg/l, which may result in selection of resistant HIV-1 viral strains. Therefore, boosting of saquinavir by ketoconazole is not recommended.
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July 2007

Interindividual variability of once-daily ritonavir boosted saquinavir pharmacokinetics in Thai and UK patients.

J Antimicrob Chemother 2005 Nov 4;56(5):908-13. Epub 2005 Oct 4.

The HIV Netherlands Australia Thailand Research Collaboration, Thai Red Cross Aids Research Centre, Bangkok, 104 Rajdumri Road, 10330 Pathumwan, Bangkok, Thailand.

Objectives: Differential exposure to saquinavir/ritonavir may lead to therapy failure. The objective was to identify factors that influence variability of saquinavir/ritonavir plasma concentrations.

Methods: Saquinavir/ritonavir data, dosed as 1600/100 mg once daily, from three separate pharmacokinetic studies, in 45 patients from Thailand and the UK, were pooled. Pharmacokinetic parameters were based on non-compartmental analysis. Univariate analysis was performed with saquinavir as the dependent variable, and ritonavir area under the curve (AUC), gender, body weight, body mass index (BMI) and study site as independent variables. Variables with a P value <0.10 were included in a multivariate linear regression analysis.

Results: Higher saquinavir AUCs, maximum concentrations (Cmax) and minimum concentrations (Cmin) were seen in Thai patients than in UK patients. Univariate analysis showed associations between body weight, gender, study site and ritonavir AUC and saquinavir AUC (P < 0.05), whereas BMI (P = 0.13) did not. In the multivariate analysis, ritonavir AUC (P = 0.0001) and study site (P = 0.0021) were significantly related to saquinavir AUC (R2 = 0.50).

Conclusions: The ritonavir AUC and study site appeared to be related to exposure of saquinavir. Study site should be viewed as the total of country- and study-specific differences--such as differences in lifestyle, environment, genetic background and dietary composition--between the analysed studies.
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November 2005