Population Pharmacokinetic Properties of Piperaquine in Falciparum Malaria: An Individual Participant Data Meta-Analysis.

BACKGROUND: Artemisinin-based combination therapies (ACTs) are the mainstay of the current treatment of uncomplicated Plasmodium falciparum malaria, but ACT resistance is spreading across Southeast Asia. Dihydroartemisinin-piperaquine is one of the five ACTs currently recommended by the World Health Organization. Previous studies suggest that young children (<5 y) with malaria are under-dosed. This study utilised a population-based pharmacokinetic approach to optimise the antimalarial treatment regimen for piperaquine. METHODS AND FINDINGS: Published pharmacokinetic studies on piperaquine were identified through a systematic literature review of articles published between 1 January 1960 and 15 February 2013. Individual plasma piperaquine concentration-time data from 11 clinical studies (8,776 samples from 728 individuals) in adults and children with uncomplicated malaria and healthy volunteers were collated and standardised by the WorldWide Antimalarial Resistance Network. Data were pooled and analysed using nonlinear mixed-effects modelling. Piperaquine pharmacokinetics were described successfully by a three-compartment disposition model with flexible absorption. Body weight influenced clearance and volume parameters significantly, resulting in lower piperaquine exposures in small children (<25 kg) compared to larger children and adults (≥25 kg) after administration of the manufacturers' currently recommended dose regimens. Simulated median (interquartile range) day 7 plasma concentration was 29.4 (19.3-44.3) ng/ml in small children compared to 38.1 (25.8-56.3) ng/ml in larger children and adults, with the recommended dose regimen. The final model identified a mean (95% confidence interval) increase of 23.7% (15.8%-32.5%) in piperaquine bioavailability between each piperaquine dose occasion. The model also described an enzyme maturation function in very young children, resulting in 50% maturation at 0.575 (0.413-0.711) y of age. An evidence-based optimised dose regimen was constructed that would provide piperaquine exposures across all ages comparable to the exposure currently seen in a typical adult with standard treatment, without exceeding the concentration range observed with the manufacturers' recommended regimen. Limited data were available in infants and pregnant women with malaria as well as in healthy individuals. CONCLUSIONS: The derived population pharmacokinetic model was used to develop a revised dose regimen of dihydroartemisinin-piperaquine that is expected to provide equivalent piperaquine exposures safely in all patients, including in small children with malaria. Use of this dose regimen is expected to prolong the useful therapeutic life of dihydroartemisinin-piperaquine by increasing cure rates and thereby slowing resistance development. This work was part of the evidence that informed the World Health Organization technical guidelines development group in the development of the recently published treatment guidelines (2015).

Population Pharmacokinetics and Pharmacodynamics of Lumefantrine in Young Ugandan Children Treated With Artemether-Lumefantrine for Uncomplicated Malaria.

BACKGROUND: The pharmacokinetics and pharmacodynamics of lumefantrine, a component of the most widely used treatment for malaria, artemether-lumefantrine, has not been adequately characterized in young children. METHODS: Capillary whole-blood lumefantrine concentration and treatment outcomes were determined in 105 Ugandan children, ages 6 months to 2 years, who were treated for 249 episodes of Plasmodium falciparum malaria with artemether-lumefantrine. RESULTS: Population pharmacokinetics for lumefantrine used a 2-compartment open model with first-order absorption. Age had a significant positive correlation with bioavailability in a model that included allometric scaling. Children not receiving trimethoprim-sulfamethoxazole with capillary whole blood concentrations <200 ng/mL had a 3-fold higher hazard of 28-day recurrent parasitemia, compared with those with concentrations >200 ng/mL (P = .0007). However, for children receiving trimethoprim-sulfamethoxazole, the risk of recurrent parasitemia did not differ significantly on the basis of this threshold. Day 3 concentrations were a stronger predictor of 28-day recurrence than day 7 concentrations. CONCLUSIONS: We demonstrate that age, in addition to weight, is a determinant of lumefantrine exposure, and in the absence of trimethoprim-sulfamethoxazole, lumefantrine exposure is a determinant of recurrent parasitemia. Exposure levels in children aged 6 months to 2 years was generally lower than levels published for older children and adults. Further refinement of artemether-lumefantrine dosing to improve exposure in infants and very young children may be warranted.

Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and antifactor Xa activity.

BACKGROUND: Morbidly obese patients undergoing gastric bypass surgery are at risk for postoperative venous thromboembolism. Evidence-based recommendations regarding the dosing and duration of thromboprophylaxis are lacking for morbidly obese surgical patients. The aims of this study were to evaluate the safety and efficacy of an extended duration, body mass index (BMI)-stratified enoxaparin thromboprophylaxis regimen in patients undergoing Roux-en-Y gastric bypass and to determine the resultant antifactor Xa (AFXa) activity in morbidly obese surgical patients. METHODS: In this prospective open trial, 223 patients (75% female, mean BMI 50.4 kg/m2) undergoing Roux-en-Y gastric bypass were assigned to receive enoxaparin 40 mg (BMI 50 kg/m2), n = 99) every 12 hours during hospitalization and once daily for 10 days after discharge. The AFXa levels were monitored serially, and dose adjustments were made for results outside the target prophylactic range (.2-.4 IU/mL +/- 10%) after the third dose. The safety and efficacy outcomes were major bleeding and venous thromboembolism. RESULTS: Roux-en-Y gastric bypass was performed laparoscopically in 208 subjects (93%). The duration of surgery averaged 99.5 +/- 31 minutes, and the median length of hospitalization was 3 days. Target prophylactic AFXa concentration was achieved by 74% of patients after the third enoxaparin dose; none reached the full anticoagulation concentration. One patient developed nonfatal venous thromboembolism (.45%). Four patients required transfusion (1.79%). Bleeding was not associated with a high AFXa concentration. CONCLUSION: This BMI-stratified, extended enoxaparin dosing regimen provided well-tolerated, effective prophylaxis against venous thromboembolism in patients undergoing gastric bypass surgery.

Pharmacokinetics of single-dose levonorgestrel in adolescents.

PURPOSE: The purpose of this study is to compare the pharmacokinetics of levonorgestrel, a drug used for emergency contraception between female adolescents and adults. METHODS: Twenty-two female subjects, aged 13-16 years, received a single 0.75-mg dose of the drug. Serial blood samples were collected for 72 h and used to measure plasma levonorgestrel concentrations. Previously published data from 16 adults, aged 18-45 years, served as comparison. RESULTS: There was a statistically significant higher total plasma clearance divided by the bioavailability (CL/F) of levonorgestrel in adolescents compared to adults, resulting in lower maximum and average total plasma concentrations. There was a trend for a larger volume of distribution divided by bioavailability (V/F), but there was no significant difference in the half-life of levonorgestrel in adolescents relative to adults (p=.098). CONCLUSION: The differences between adolescents and adults are unlikely to be clinically significant because specific changes in total concentrations suggest that unbound concentrations are probably not affected. Furthermore, empirically high doses of levonorgestrel are given for emergency contraception.

Rethinking Dosing Regimen Selection of Piperaquine for Malaria Chemoprevention: A Simulation Study.

BACKGROUND: The combination of short-acting dihydroartemisinin and long-acting piperaquine (DP) is among the first-line therapies for the treatment of uncomplicated Plasmodium falciparum malaria. Population pharmacokinetic models of piperaquine (PQ) based on data from acute treatment of young children can be used to predict exposure profiles of piperaquine under different DP chemoprevention regimens. The purpose of our study was to make such predictions in young children. METHODS: Based on a prior population pharmacokinetic model of PQ in young Ugandan children, we simulated capillary plasma concentration-time profiles (including their variability) of candidate chemoprevention regimens for a reference population of 1-2 year olds weighing at least 11 kg. Candidate regimens that were tested included monthly administration of standard therapeutic doses, bimonthly dosing, and weekly dosing (with and without a loading dose). RESULTS: Once daily doses of 320 mg for three days (960 mg total) at the beginning of each month are predicted to achieve an average steady-state trough capillary piperaquine concentration of 35 ng/mL, with 60% achieving a level of 30 ng/mL or higher. In contrast, weekly dosing of 320 mg (i.e., 33% higher amount per month) is predicted to approximately double the average steady-state trough concentration, increase the percent of children predicted to achieve 30 ng/mL or higher (94%), while at the same time lowering peak concentrations. Exposure at steady-state, reached at approximately 3 months of multiple dosing, is expected to be approximately 2-fold higher than exposure following initial dosing, due to accumulation. A loading dose improves early exposure, thereby reducing the risk of breakthrough infections at the initiation of chemoprevention. CONCLUSIONS: Once weekly chemoprevention of DP predicts favourable exposures with respect to both trough and peak concentrations. These predictions need to be verified, as well as safety evaluated, in field-based clinical studies of young children. Simulations based on prior knowledge provide a systematic information-driven approach to evaluate candidate DP chemopreventive regimens for future trial designs.