Dihydroartemisinin (DHA)‐piperaquine is promising for malaria chemoprevention in pregnancy. We assessed the impacts of pregnancy and efavirenz‐based antiretroviral therapy on exposure to DHA and ...piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV‐uninfected pregnant women, in 27 HIV‐infected pregnant women receiving efavirenz, and in 30 HIV‐uninfected nonpregnant women. DHA peak concentration and area under the concentration time curve (AUC0‐8hr) were 50% and 47% lower, respectively, and piperaquine AUC0‐21d was 40% lower in pregnant women compared to nonpregnant women. DHA AUC0‐8hr and piperaquine AUC0‐21d were 27% and 38% lower, respectively, in pregnant women receiving efavirenz compared to HIV‐uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed.
Objectives
To determine the characteristics of the binding of nelfinavir and active M8 to α1‐acid glycoprotein (AAG) and human serum albumin (HSA), and to examine the displacement effects of drugs ...binding extensively to AAG (ritonavir and saquinavir) or to HSA (salicylic acid and valproic acid).
Methods
Free drugs were separated by equilibrium dialysis after incubation with human plasma or purified plasma proteins and after co‐incubation with potential displacers. Association constants were estimated from double‐reciprocal plots of the data.
Results
Nelfinavir and M8 free fractions fractions of unbound drug (fus) were 0.42±0.08% (mean±standard deviation) and 0.64±0.07%, respectively. For the two analytes, respectively, association constants were 7.25 × 107/m and 3.33 × 107/m for AAG and 1.11 × 106/m and 7.92 × 105/m for HSA. Nelfinavir fu in an AAG solution was significantly (P<0.01) increased by the addition of ritonavir or saquinavir, whereas it was unaltered by addition of these drugs to whole plasma. Similarly, fu in an HSA solution was significantly increased (P<0.01) by the addition of salicylic acid or valproic acid, whereas there was no difference in the free fraction in plasma.
Conclusions
The affinity of nelfinavir for human plasma proteins was higher than that of M8, and both nelfinavir and M8 showed higher affinity to AAG than to HSA. The free fraction of nelfinavir was not affected by drugs that bind extensively to AAG or albumin when these drugs were added to whole plasma in combination, suggesting a compensatory effect of alternate binding proteins.
Therapy with HIV protease inhibitors (PI) causes insulin resistance even in the absence of HIV infection, hyperlipidemia or changes in body composition. The mechanism of the effects on insulin action ...is unknown. In vitro studies suggest that PI selectively and rapidly inhibit the activity of the insulin-responsive glucose transporter GLUT-4. We hypothesized that a single dose of the PI indinavir resulting in therapeutic plasma concentrations would acutely decrease insulin-stimulated glucose disposal in healthy human volunteers.
Randomized, double-blind, cross-over study comparing the effect of 1200 mg of orally administered indinavir and placebo on insulin-stimulated glucose disposal during a 180-min euglycemic, hyperinsulinemic clamp. Six healthy HIV-seronegative adult male volunteers were studied twice with 7 to 10 days between studies.
There were no significant differences in baseline fasting body weight, or plasma glucose, insulin, lipid and lipoprotein levels between placebo- and indinavir-treated subjects. During steady-state (t60-180 min) insulin reached comparable levels (394 +/- 13 versus 390 +/- 11 pmol/l) and glucose was clamped at approximately 4.4 mmol/l under both conditions. The average maximum concentration of indinavir was 9.4 +/- 2.2 microM and the 2-h area under the curve was 13.5 +/- 3.1 microM.h. Insulin-stimulated glucose disposal per unit of insulin (M/I) decreased in all subjects from 14.1 +/- 1.2 to 9.2 +/- 0.8 mg/kg.min per microUI/ml (95% confidence interval for change, 3.7-6.1; P < 0.001) on indinavir (average decrease, 34.1 +/- 9.2%). The non-oxidative component of total glucose disposal (storage) decreased from 3.9 +/- 1.8 to 1.9 +/- 0.9 mg/kg.min (P < 0.01). Free fatty acid levels were not significantly different at baseline and were suppressed equally with insulin administration during both studies.
A single dose of indinavir acutely decreases total and non-oxidative insulin-stimulated glucose disposal during a euglycemic, hyperinsulinemic clamp. Our data are compatible with the hypothesis that an acute effect of indinavir on glucose disposal in humans is mediated by a direct blockade of GLUT-4 transporters.
This prospective trial investigated the population pharmacokinetics of piperaquine given with dihydroartemisinin to treat uncomplicated malaria in 107 Ugandan children 6 months to 2 years old, an age ...group previously unstudied. Current weight‐based dosing does not adequately address physiological changes in early childhood. Patients were administered standard 3‐day oral doses and provided 1,282 capillary plasma concentrations from 218 malaria episodes. Less than 30% of treatments achieved 57 ng/mL on day 7. A three‐compartment model with first‐order absorption described the data well. Age had a statistically significant effect (P < 0.005) on clearance/bioavailability in a model that accounts for allometric scaling. Simulations demonstrated that higher doses in all children, but especially in those with lower weight for age, are required for adequate piperaquine exposure, although safety and tolerance will need to be established. These findings support other evidence that both weight‐ and age‐specific guidelines for piperaquine dosing in children are urgently needed.
Therapy with HIV protease inhibitors (PI) has been shown to worsen glucose and lipid metabolism, but whether these changes are caused by direct drug effects, changes in disease status, or body ...composition is unclear. Therefore, we tested the effects of the PI combination lopinavir and ritonavir on glucose and lipid metabolism in HIV-negative subjects.
A dose of 400 mg lopinavir/100 mg ritonavir was given twice a day to 10 HIV-negative men. Fasting glucose and insulin, lipid and lipoprotein profiles, oral glucose tolerance, insulin sensitivity by euglycemic hyperinsulinemic clamp, and body composition were determined before and after lopinavir/ritonavir treatment for 4 weeks.
On lopinavir/ritonavir, there was an increase in fasting triglyceride (0.89 +/- 0.15 versus 1.63 +/- 0.36 mmol/l; P = 0.007), free fatty acid (FFA; 0.33 +/- 0.04 versus 0.43 +/- 0.06 mmol/l; P = 0.001), and VLDL cholesterol (15.1 +/- 2.6 versus 20 +/- 3.3 mg/dl; P = 0.05) levels. There were no changes in fasting LDL, HDL, IDL, lipoprotein (a), or total cholesterol levels. Fasting glucose, insulin, and insulin-mediated glucose disposal were unchanged, but on a 2 h oral glucose tolerance test glucose and insulin increased. There were no changes in weight, body fat, or abdominal adipose tissue by computed tomography.
Treatment with 4 weeks of lopinavir/ritonavir in HIV-negative men causes an increase in triglyceride levels, VLDL cholesterol, and FFA levels. Lopinavir/ritonavir leads to a deterioration in glucose tolerance at 2 h, but there is no significant change in insulin-mediated glucose disposal rate by euglycemic hyperinsulinemic clamp.
Cannabinoid use could potentially alter HIV RNA levels by two mechanisms: immune modulation or cannabinoid-protease inhibitor interactions (because both share cytochrome P-450 metabolic pathways).
To ...determine the short-term effects of smoked marijuana on the viral load in HIV-infected patients.
Randomized, placebo-controlled, 21-day intervention trial.
The inpatient General Clinical Research Center at the San Francisco General Hospital, San Francisco, California.
67 patients with HIV-1 infection.
Participants were randomly assigned to a 3.95%-tetrahydrocannabinol marijuana cigarette, a 2.5-mg dronabinol (delta-9-tetrahydrocannabinol) capsule, or a placebo capsule three times daily before meals.
HIV RNA levels, CD4+ and CD8+ cell subsets, and pharmacokinetic analyses of the protease inhibitors.
62 study participants were eligible for the primary end point (marijuana group, 20 patients; dronabinol group, 22 patients; and placebo group, 20 patients). Baseline HIV RNA level was less than 50 copies/mL for 36 participants (58%), and the median CD4+ cell count was 340 x 109 cells/L. When adjusted for baseline variables, the estimated average effect versus placebo on change in log10 viral load from baseline to day 21 was -0.07 (95% CI, -0.30 to 0.13) for marijuana and -0.04 (CI, -0.20 to 0.14) for dronabinol. The adjusted average changes in viral load in marijuana and dronabinol relative to placebo were -15% (CI, -50% to 34%) and -8% (CI, -37% to 37%), respectively. Neither CD4+ nor CD8+ cell counts appeared to be adversely affected by the cannabinoids.
Smoked and oral cannabinoids did not seem to be unsafe in people with HIV infection with respect to HIV RNA levels, CD4+ and CD8+ cell counts, or protease inhibitor levels over a 21-day treatment.
Objectives
Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6‐β hydroxycortisol to cortisol (6βHF : ...F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)‐treated HIV‐1‐infected women and to relate this change to ARV pharmacokinetics.
Methods
Women receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (> 30 weeks) and postpartum with determination of 6βHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau.
Results
6βHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P = 0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum vs. postpartum 6βHF : F comparison was marginally significant (P = 0.058). When the change in the 6βHF : F ratio was related to the change in the dose‐adjusted ARV area under the plasma concentration vs. time curve (AUC) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (LPV/r) arms demonstrated an inverse relationship (P = 0.125), albeit this correlation did not reach statistical significance.
Conclusions
A 35% increase in the urinary 6βHF : F ratio was measured during late pregnancy compared with postpartum, indicating that CYP3A induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6βHF : F ratio and the change in the LPV AUC antepartum vs. postpartum suggests that CYP3A induction may be one mechanism behind altered LPV exposure during pregnancy.
Background
Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and α‐1 acid glycoprotein (AAG). Small changes in PB can ...greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to ≥1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously.
Methods
P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP.
Results
AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96±0.16% AP vs. 0.82±0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG.
Conclusions
LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.
Protease inhibitor (PI)-based combination antiretroviral therapy is often indicated for treatment of maternal HIV disease, but little is known about PI pharmacokinetics during pregnancy. Increased ...cytochrome P450 activity may affect the disposition of PI and decrease drug exposure.
Steady-state PI pharmacokinetics, measured by the area under the plasma concentration versus time curve (AUC(tau)), were evaluated in women on stable antiretroviral regimens containing nelfinavir (n = 9) or indinavir (n = 4) with or without ritonavir (n = 2) during the second and third trimesters of pregnancy and postpartum. Cytochrome P450 activity was assessed by measuring the urine 6 beta-hydroxycortisol to cortisol ratio (6 beta-OHF/F).
AUC(tau) in women on indinavir alone decreased and 6 beta-OHF/F ratios increased during pregnancy compared with postpartum control values (n = 2). Nelfinavir results demonstrated no clear change and were highly variable.
The results for indinavir suggest that metabolic induction occurs during pregnancy, which apparently resolves spontaneously postpartum. This may warrant dosage adjustment during pregnancy. This induction is offset by concomitant use of ritonavir. Nelfinavir results were variable and, therefore, the impact of pregnancy on nelfinavir disposition was not fully determined.
The use of cannabinoids for appetite stimulation and the management of wasting and antiretroviral side-effects has become a common practice in the care of HIV-infected individuals. We present ...pharmacokinetic data from a randomized placebo-controlled study designed to evaluate the metabolic effects of smoked marijuana and dronabinol in HIV-infected patients receiving indinavir (IDV) or nelfinavir (NFV).
Subjects on stable regimens containing IDV 800 mg every 8 h (n = 28) or NFV 750 mg three time a day (n = 34) were randomized to one of three treatment arms: 3.95% THC marijuana cigarettes, dronabinol 2.5 mg capsules or placebo capsules administered three times daily. Serial blood sampling was performed at baseline and on day 14 of treatment. The changes in NFV and IDV pharmacokinetics were measured as the median percentage change from baseline.
At day 14, the 8-h area under the curve (AUC(8)) changed by -10.2% (P = 0.15), maximum concentration (C(max)) by -17.4% (P = 0.46), and minimum concentration (C(min)) by -12.2% (P = 0.28) for patients in the NFV marijuana arm (n = 11). Similar decreases had occurred by day 14 among patients in the IDV marijuana arm (n = 9): AUC8 had changed by -14.5% (P = 0.074), C(max) by -14.1% (P = 0.039), and C(min) by -33.7% (P = 0.65).
Despite a statistically significant decrease in C(max) of IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.
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