Pharmacokinetic study of saquinavir hard gel caps/ritonavir in HIV-1-infected patients: 1600/100 mg once-daily compared with 2000/100 mg once-daily and 1000/100 mg twice-daily

Objectives: A pharmacokinetic comparison of three dosing regimens of saquinavir/ritonavir was carried out: 1600/100 mg once-daily with 1000/100 mg twice-daily, and 1600/100 mg once-daily with 2000/100 mg once-daily. Methods: Twenty patients on saquinavir hard gel caps/ritonavir 1600/100 mg once-daily in combination with two nucleoside reverse transcriptase inhibitors for at least 4 weeks were enrolled and randomized to either saquinavir hard gel caps/ritonavir 1000/100 mg twice-daily or 2000/100 mg once-daily. Two pharmacokinetic curves were plotted, at baseline (day 0) and 7 days after the switch. Plasma concentrations were measured at 0, 2, 4, 6, 8, 10, 12 (and 24 for once-daily dosing) hours after drug intake by validated high-performance liquid chromatographic assay (HPLC). The area under the plasma concentration-time curve (AUC0-24 or AUC0-12), maximum and minimum concentration (Cmax and Cmin) and elimination half-life were calculated using a non-compartmental model. Results: Compared with saquinavir/ritonavir 1600/100 mg once-daily dosing, the saquinavir AUC and Cmin improved significantly when dosed as 1000/100 mg twice-daily (53% and 299%, respectively), and as 2000/100 mg once-daily (71% and 65%, respectively). Low Cmin in three subjects at baseline was corrected after switch to the other dosages. Saquinavir/ritonavir 2000/100 mg once-daily was also associated with a significant increase in saquinavir Cmax (52%) compared with saquinavir/ritonavir 1600/100 mg once-daily. Conclusions: Saquinavir/ritonavir when dosed as 2000/100 mg once-daily or 1000/100 mg twice-daily achieves higher saquinavir plasma levels compared with saquinavir/ritonavir 1600/100 mg once-daily. Taking the convenience of once-daily dosing into consideration, dosage of 2000/100 mg once-daily may be preferre

Relationships between drug exposure, changes in metabolic parameters and body fat in HIV-infected patients switched to a nucleoside sparing regimen.

Contains fulltext : 53680.pdf (publisher's version ) (Closed access)BACKGROUND: The pathogenesis of metabolic disturbances in treated HIV infection is incompletely understood. METHODS: Relationships between fasted metabolic parameters, body composition, and drug plasma concentrations were investigated in 59 patients who switched from failed nucleoside analogue treatment to ritonavir-boosted indinavir and efavirenz therapy. Metabolic parameters, peripheral fat, visceral adipose tissue (VAT) and drug plasma concentrations were measured prospectively. RESULTS: Ritonavir exposure was found to be negatively correlated with high-density lipoprotein cholesterol (HDL-c) changes, with a 2.4% decrease in HDL-c for each unit increase in ritonavir concentration ratio. Significant associations between indinavir or efavirenz concentrations and metabolic disturbances were not observed. Total cholesterol (TC) correlated positively with high body mass index (BMI) and negatively with baseline limb fat mass: each unit increase in BMI and each kilogram reduction in baseline limb fat corresponded with a TC increase of 2.4% and 4.1%, respectively. Baseline triglyceride levels were lower in those patients with relatively greater limb fat mass: each kilogram reduction of total limb fat mass was associated with a 15.7% increase in triglyceride concentration. Changes in VAT were positively correlated with TC: for every unit TC increase a 0.3% VAT increase was observed (over 48 weeks). CONCLUSIONS: Reduced limb fat mass at the start of the study treatment, increases in VAT mass, and higher plasma concentrations of ritonavir on study treatment were each--to varying degrees--associated with various metabolic disturbances

Pharmacokinetic study of saquinavir hard gel caps/ritonavir in HIV-1-infected patients: 1600/100 mg once-daily compared with 2000/100 mg once-daily and 1000/100 mg twice-daily.

Contains fulltext : 57124.pdf (publisher's version ) (Closed access)OBJECTIVES: A pharmacokinetic comparison of three dosing regimens of saquinavir/ritonavir was carried out: 1600/100 mg once-daily with 1000/100 mg twice-daily, and 1600/100 mg once-daily with 2000/100 mg once-daily. METHODS: Twenty patients on saquinavir hard gel caps/ritonavir 1600/100 mg once-daily in combination with two nucleoside reverse transcriptase inhibitors for at least 4 weeks were enrolled and randomized to either saquinavir hard gel caps/ritonavir 1000/100 mg twice-daily or 2000/100 mg once-daily. Two pharmacokinetic curves were plotted, at baseline (day 0) and 7 days after the switch. Plasma concentrations were measured at 0, 2, 4, 6, 8, 10, 12 (and 24 for once-daily dosing) hours after drug intake by validated high-performance liquid chromatographic assay (HPLC). The area under the plasma concentration-time curve (AUC0-24 or AUC0-12), maximum and minimum concentration (Cmax and Cmin) and elimination half-life were calculated using a non-compartmental model. RESULTS: Compared with saquinavir/ritonavir 1600/100 mg once-daily dosing, the saquinavir AUC and Cmin improved significantly when dosed as 1000/100 mg twice-daily (53% and 299%, respectively), and as 2000/100 mg once-daily (71% and 65%, respectively). Low Cmin in three subjects at baseline was corrected after switch to the other dosages. Saquinavir/ritonavir 2000/100 mg once-daily was also associated with a significant increase in saquinavir Cmax (52%) compared with saquinavir/ritonavir 1600/100 mg once-daily. CONCLUSIONS: Saquinavir/ritonavir when dosed as 2000/100 mg once-daily or 1000/100 mg twice-daily achieves higher saquinavir plasma levels compared with saquinavir/ritonavir 1600/100 mg once-daily. Taking the convenience of once-daily dosing into consideration, dosage of 2000/100 mg once-daily may be preferred

Nevirapine plasma concentrations and concomitant use of rifampin in patients coinfected with HIV-1 and tuberculosis.

OBJECTIVES: In countries with high numbers of HIV/tuberculosis coinfection nevirapine and rifampin are used extensively. However, limited data are available about whether or not nevirapine and rifampin can be safely coadministered without the plasma concentration of nevirapine falling below therapeutic levels. METHODS: Blood samples for determination of nevirapine plasma concentrations were collected from patients using nevirapine 200 mg twice daily with or without concomitant rifampin. Bivariate and multivariate linear regression models were used to investigate factors possibly related to nevirapine concentrations. RESULTS: We received 74 blood samples from patients using nevirapine plus rifampin, and collected blood samples from an equal number of controls using nevirapine only. Groups were similar for age, gender, weight, height and body mass index (BMI). In the rifampin group the mean nevirapine concentration was 5.47 +/- 2.66 mg/l, whereas in the control group the mean nevirapine concentration was 8.72 +/- 3.98 mg/l. In the rifampin group seven nevirapine trough concentrations were low ( 3.1 mg/l. Our results suggest that from a pharmacological point of view the majority of Thai coinfected patients, who have low BMIs, reach nevirapine plasma concentrations that are adequate for treatment of HIV. However this can only be undertaken if nevirapine plasma concentration monitoring is available and can be closely followed

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

Item does not contain fulltextOBJECTIVES: 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