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ABSTRACTIntroduction: RTS,S/AS01 is currently the most advanced malaria vaccine but provides incomplete, short-term protection. It was developed for use within the expanded program on immunizations (EPI) for African children. Another use could be adding mass RTS,S/AS01 vaccination to the integrated malaria elimination strategy in the Greater Mekong Subregion (GMS), where multidrug-resistant P.falciparumstrains have emerged and spread. Prior to evaluating RTS,S/AS01 in large-scale trials we assessed whether the vaccine, administered with and without antimalarial drugs, is safe and immunogenic in Asian populations.Methods: An open-label, randomized, controlled phase 2 trial was conducted in healthy, adult Thai volunteers. Seven vaccine regimens with and without antimalarial drugs (dihydroartemisinin-piperaquine plus a single low dose primaquine) were assessed. Antibody titres against the PfCSP full-length (NANP) 6, PfCSP anti-C–term, PfCSP full-length (N + C-Terminal) were measured by standard enzyme-linked immunosorbent assays. Liquid chromatography was used to measure piperaquine, primaquine and carboxy-primaquine concentrations.Results: 193 volunteers were enrolled and 186 study participants completed the 6 months follow-up period. One month after the last vaccination all study participants had seroconverted to the PfCSP (NANP)6, and the PfCSP Full Length (N + C-Terminal). More than 90% had seroconverted to the Pfanti-C-Term CSP. There was no indication that drug concentrations were influenced by vaccine regimens or the antibody levels by the drug regimens. Adverse events were similarly distributed between the seven treatment groups. No serious adverse events attributable to the study interventions were detected.Conclusion: This study found that RTS,S/AS01 with and without dihydroartemisinin-piperaquine plus a single low dose primaquine was safe and immunogenic in a healthy, adult Asian population.

Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparummalaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress.

ABSTRACTAmodiaquine is effective for the treatment of Plasmodium vivaxmalaria, but there is little information on the pharmacokinetic and pharmacodynamic properties of amodiaquine in pregnant women with malaria. This study evaluated the population pharmacokinetic and pharmacodynamic properties of amodiaquine and its biologically active metabolite, desethylamodiaquine, in pregnant women with P. vivaxinfection and again after delivery. Twenty-seven pregnant women infected with P. vivaxmalaria on the Thai-Myanmar border were treated with amodiaquine monotherapy (10 mg/kg/day) once daily for 3 days. Nineteen women, with and without P. vivaxinfections, returned to receive the same amodiaquine dose postpartum. Nonlinear mixed-effects modeling was used to evaluate the population pharmacokinetic and pharmacodynamic properties of amodiaquine and desethylamodiaquine. Amodiaquine plasma concentrations were described accurately by lagged first-order absorption with a two-compartment disposition model followed by a three-compartment disposition of desethylamodiaquine under the assumption of complete in vivoconversion. Body weight was implemented as an allometric function on all clearance and volume parameters. Amodiaquine clearance decreased linearly with age, and absorption lag time was reduced in pregnant patients. Recurrent malaria infections in pregnant women were modeled with a time-to-event model consisting of a constant-hazard function with an inhibitory effect of desethylamodiaquine. Amodiaquine treatment reduced the risk of recurrent infections from 22.2% to 7.4% at day 35. In conclusion, pregnancy did not have a clinically relevant impact on the pharmacokinetic properties of amodiaquine or desethylamodiaquine. No dose adjustments are required in pregnancy.

Artemisinin-resistant falciparum malaria has arisen in western Cambodia. A concerted international effort is underway to contain artemisinin-resistant Plasmodium falciparum, but containment strategies are dependent on whether resistance has emerged elsewhere. We aimed to establish whether artemisinin resistance has spread or emerged on the Thailand–Myanmar (Burma) border.

Many women in resource-poor settings lack access to reliable gestational age assessment because they do not know their last menstrual period; there is no ultrasound (US) and methods of newborn gestational age dating are not practised by birth attendants. A bespoke multiple-measures model was developed to predict the expected date of delivery determined by US. The results are compared with both a linear and a nonlinear model. Prospectively collected early US and serial symphysis-pubis fundal height (SFH) data were used in the models. The data were collected from Karen and Burmese women attending antenatal care on the Thai–Burmese border. The multiple-measures model performed best, resulting in a range of accuracy depending on the number of SFH measures recorded per mother (for example six SFH measurements resulted in a prediction accuracy of ±2 weeks). SFH remains the proxy for gestational age in much of the resource-poor world. While more accurate measures should be encouraged, we demonstrate that a formula that incorporates at least three SFH measures from an individual mother and the slopes between them provide a significant increase in the accuracy of prediction compared with the linear and nonlinear formulae also using multiple SFH measures.

ABSTRACTIntermittent preventive treatment (IPT) is increasingly used to reduce malaria morbidity and mortality in children and pregnant women. The efficacy of IPT depends on the pharmacokinetic and pharmacodynamic properties of the antimalarial drugs used. Healthy adult male volunteers whose occupation put them at high risk of malaria on the Northwest border of Thailand were randomized to receive a 3-day-treatment dose of dihydroartemisinin-piperaquine monthly (DPm) or every 2 months (DPalt) or an identical placebo with or without fat (6.4g/dose) over a 9-month period. All volunteers were monitored weekly. One thousand adults were recruited. Dihydroartemisinin-piperaquine was well tolerated. There were 114 episodes of malaria (49 Plasmodium falciparum, 63 P. vivax, and 2 P. ovale). The protective efficacy against all malaria at 36 weeks was 98% (95% confidence interval [CI], 96% to 99%) in the DPm group and 86% (95% CI, 81% to 90%) in the DPalt group (for both, P< 0.0001 compared to the placebo group). As a result, the placebo group also had lower hematocrits during the study (P< 0.0001). Trough plasma piperaquine concentrations were the main determinant of efficacy; no malaria occurred in participants with a trough concentration above 31 ng/ml. Neither plasma piperaquine concentration nor efficacy was influenced by the coadministration of fat. DPm is safe to use and is effective in the prevention of malaria in adult males living in an area where P. vivaxand multidrug-resistant P. falciparummalaria are endemic.

ABSTRACTDihydroartemisinin-piperaquine is a fixed-dose artemisinin-based combination treatment. Some antimalarials have altered pharmacokinetics in pregnancy. Pregnant women in the 2nd or 3rd trimester and matched nonpregnant women with uncomplicated falciparum malaria were treated with a total of 6.4 mg/kg of body weight dihydroartemisinin and 51.2 mg/kg piperaquine once daily for 3 days. Venous blood samples were drawn at prespecified time points over 9 weeks. Plasma dihydroartemisinin and piperaquine concentrations were analyzed by liquid chromatography-mass spectrometry. Piperaquine and dihydroartemisinin pharmacokinetics were well described. There were no significant differences in total piperaquine exposure (P= 0.80) or drug exposure during the terminal elimination phase (72 h to infinity) (P= 0.64) between the two groups. The apparent volume of distribution of piperaquine was significantly smaller (602 liters/kg versus 877 liters/kg) in pregnant women than in nonpregnant women (P= 0.0057), and the terminal elimination half-life was significantly shorter (17.8 days versus 25.6 days; P= 0.0023). Dihydroartemisinin exposure after the first dose was significantly lower (844 h × ng/ml versus 1,220 h × ng/ml, P= 0.0021) in pregnant women, but there were no significant differences in total dihydroartemisinin exposure or maximum concentrations between the two groups. There were no significant differences in any pharmacokinetic parameters between the second and third trimester. These results obtained through noncompartmental analysis suggest that in the treatment of falciparum malaria, there are no clinically important differences in the pharmacokinetics of dihydroartemisinin or piperaquine between pregnant and nonpregnant women. However, a more detailed analysis using population pharmacokinetic modeling is needed to fully investigate the differences found for some of the pharmacokinetic parameters, such as the terminal half-life.

ABSTRACTDihydroartemisinin-piperaquine is a new, highly effective, and well-tolerated combination treatment for uncomplicated falciparum malaria. The lipophilic characteristic of piperaquine suggests that administration together with fat will increase the oral bioavailability of the drug, and this has been reported for healthy volunteers. This pharmacokinetic study monitored 30 adult patients with uncomplicated falciparum malaria for 4.5 months to evaluate the effects of the concomitant intake of fat on the total piperaquine exposure. The fixed-drug combination of dihydroartemisinin-piperaquine was given with water to fasting patients (n= 15) or was coadministered with 200 ml milk containing 6.4 g fat (n= 15). The drug combination was generally well tolerated, and there were no severe adverse effects reported for either group during the study. Total piperaquine exposure (area under the concentration-time curve from zero to infinity [AUC0-∞]; results are given as medians [ranges]) were not statistically different between fed (29.5 h · μg/ml [20.6 to 58.7 h · μg/ml]) and fasting (23.9 h · μg/ml [11.9 to 72.9 h · μg/ml]) patients, but the interindividual variation was reduced in the fed group. Overall, none of the pharmacokinetic parameters differed statistically between the groups. Total piperaquine exposure correlated well with the day 7 concentrations in the fasted group, but the fed group showed a poor correlation. In conclusion, the coadministration of 6.4 g fat did not have any significant effect on piperaquine pharmacokinetics in the treatment of uncomplicated malaria.

ABSTRACTThere is no parenteral formulation of the neuraminidase inhibitor oseltamivir, the most widely used anti-influenza virus drug. Oseltamivir resistance is an increasing problem. Zanamivir is effective against the most prevalent oseltamivir-resistant influenza viruses. A parenteral formulation of zanamivir is in development for the treatment of severe influenza. It is not known if there is any pharmacokinetic interaction between the two drugs. Sixteen healthy Thai adult volunteers were studied in an open-label, four-period, randomized two-sequence crossover pharmacokinetic study in which zanamivir was given by constant-rate infusion or slow intravenous injection either alone or together with oral oseltamivir. Plasma concentration profiles of oseltamivir, the active metabolite oseltamivir carboxylate, and zanamivir were measured by liquid chromatography-mass spectrometry-mass spectrometry. Both drugs were well tolerated alone and in combination. The maximum plasma concentrations and the areas under the plasma concentration-time curves (AUC) of oseltamivir and oseltamivir carboxylate were not significantly different when oseltamivir was given separately or together with zanamivir. Maximum plasma concentrations of zanamivir were 10% (95% confidence interval, 7 to 12%) higher when zanamivir was infused concurrently with oral oseltamivir than with infusions before or after oral oseltamivir. The plasma zanamivir total AUC was positively correlated with the total oseltamivir carboxylate AUC (Pearson's correlation coefficient [rP] = 0.720, P= 0.002, n= 16) but not with the oseltamivir AUC (rp= 0.121, n= 16). There is no clinically significant pharmacokinetic interaction between oseltamivir and zanamivir.

ABSTRACTIn order to study the pharmacokinetic properties of amodiaquine and desethylamodiaquine during pregnancy, 24 pregnant women in the second and third trimesters of pregnancy and with Plasmodium vivaxmalaria were treated with amodiaquine (10 mg/kg of body weight/day) for 3 days. The same women were studied again at 3 months postpartum. Plasma was analyzed for amodiaquine and desethylamodiaquine by use of a liquid chromatography-tandem mass spectrometry method. Individual concentration-time data were evaluated using noncompartmental analysis. There were no clinically relevant differences in the pharmacokinetics of amodiaquine and desethylamodiaquine between pregnant (n= 24) and postpartum (n= 18) women. The results suggest that the current amodiaquine dosing regimen is adequate for the treatment of P. vivaxinfections during pregnancy.

In this review, we consider the issues impacting conduct and design of dengue vaccine trials with reference to the recently published World Health Organization "Guidelines for Conduct of Clinical Trials of Dengue Vaccines in Endemic Areas." We discuss logistic, scientific and ethical challenges concerning evaluation and introduction of dengue vaccines; these range from randomized trials that establish "proof of concept" of vaccine efficacy, to post-"proof of concept" trials, particularly demonstration projects likely to be required for licensure or for the introduction of an already licensed vaccine into public use. We clarify and define the meaning of "proof of concept" in the clinical trial context and the meaning of terms "phase 2b", "phase 3b" and "demonstration project", which are commonly used but have not been defined well in the clinical literature.

The study aimed to compare performance between the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network (BCPNN) methods in identifying serious adverse drug reactions (ADRs) using the Thai FDA spontaneous database. The two methods were retrospectively applied to identify new, serious ADRs reported with antiretroviral therapy (ART) drugs using the data set between 1990 and 2006. We plotted the ROR and the information component against time to compare the differential timing of signal detection and the pattern of signaling over time between these methods. The ROR and the BCPNN methods identified the associations between ART drugs and serious ADRs at the same time. Both methods were similar in detecting the first signal of a potential ADR. However, the pattern of signaling seems relatively different with each method. Additional analyses of different drugs, ADRs, and databases will contribute to increase understanding of methods for postmarketing surveillance using spontaneous reporting system.

The study aimed to compare performance between the reporting odds ratio (ROR) and the Bayesian confidence propagation neural network (BCPNN) methods in identifying serious adverse drug reactions (ADRs) using the Thai FDA spontaneous database. The two methods were retrospectively applied to identify new, serious ADRs reported with antiretroviral therapy (ART) drugs using the data set between 1990 and 2006. We plotted the ROR and the information component against time to compare the differential timing of signal detection and the pattern of signaling over time between these methods. The ROR and the BCPNN methods identified the associations between ART drugs and serious ADRs at the same time. Both methods were similar in detecting the first signal of a potential ADR. However, the pattern of signaling seems relatively different with each method. Additional analyses of different drugs, ADRs, and databases will contribute to increase understanding of methods for postmarketing surveillance using spontaneous reporting system.

ABSTRACTArtemether-lumefantrine has become one of the most widely used antimalarial drugs in the world. The objective of this study was to determine the population pharmacokinetic properties of lumefantrine in pregnant women with uncomplicated multidrug-resistant Plasmodium falciparummalaria on the northwestern border of Thailand. Burmese and Karen women (n= 103) with P. falciparummalaria and in the second and third trimesters of pregnancy were treated with artemether-lumefantrine (80/480 mg) twice daily for 3 days. All patients provided five capillary plasma samples for drug quantification, and the collection times were randomly distributed over 14 days. The concentration-time profiles of lumefantrine were assessed by nonlinear mixed-effects modeling. The treatment failure rate (PCR-confirmed recrudescent infections at delivery) was high; 16.5% (95% confidence interval, 9.9 to 25.1). The population pharmacokinetics of lumefantrine were described well by a two-compartment open model with first-order absorption and elimination. The final model included interindividual variability in all pharmacokinetic parameters and a linear covariate relationship between the estimated gestational age and the central volume of distribution. A high proportion of all women (40%, 41/103) had day 7 capillary plasma concentrations of <355 ng/ml (which corresponds to approximately <280 ng/ml in venous plasma), a threshold previously associated with an increased risk of therapeutic failure in nonpregnant patients in this area. Predictive modeling suggests that a twice-daily regimen given for 5 days would be preferable in later pregnancy. In conclusion, altered pharmacokinetic properties of lumefantrine contribute to the high rates of failure of artemether-lumefantrine treatment in later pregnancy. Dose optimization is urgently needed.

Background:Artemether–lumefantrine is the most widely recommended artemisinin-based combination treatment for falciparum malaria. Quantification of artemether and its metabolite dihydroartemisinin in biological matrices has traditionally been difficult, with sensitivity being an issue. Results:A high-throughput bioanalytical method for the analysis of artemether and its metabolite dihydroartemisinin in human plasma using solid-phase extraction in the 96-well plate format and liquid chromatography coupled to positive ion mode tandem mass spectroscopy has been developed and validated according to US FDA guidelines. The method uses 50 µl plasma and covers the calibration range 1.43–500 ng/ml with a limit of detection at 0.36 ng/ml. Conclusions:The developed liquid chromatography–tandem mass spectrometry assay is more sensitive than all previous methods despite using a lower plasma volume (50 µl) and is highly suitable for clinical studies where plasma volumes are limited, such as pediatric trials.

ABSTRACTA fixed artesunate-mefloquine combination, comprising three daily doses of 8 mg of mefloquine/kg of body weight and 4 mg of artesunate/kg, has been developed recently. This study was designed to construct a population pharmacokinetic model describing this new dosage regimen of mefloquine given as loose tablets together with artesunate. In two randomized trials in Thailand which evaluated the efficacy, safety, and tolerability of this new regimen, the members of a subgroup of 50 patients were randomized to have capillary blood sampling before treatment and at five randomly assigned time points during the 63-day follow-up period. Mefloquine levels in capillary whole blood were assayed by liquid chromatography with UV detection. A pharmacokinetic model for mefloquine was constructed using mixed-effects modeling. A one-compartment model with first-order absorption and elimination was selected to describe the kinetic properties of mefloquine. For capillary whole-blood mefloquine, the area under the concentration curve (AUC) was 40% higher than previous estimates for patients given the equivalent conventional-dose regimen (mefloquine given as 15 mg/kg and then 10 mg/kg on the second and third days of treatment). The half-life (t1/2) of the carboxylic acid metabolite was estimated as 26 days, and the metabolite was eliminated more slowly than the parent drug (population t1/2estimate, 10.5 days). Splitting the 25 mg/kg dose of mefloquine into three doses of 8 mg/kg each resulted in improved oral bioavailability compared to the conventional split-dose regimen results. This new regimen is well tolerated and results in an equivalent therapeutic response.

ABSTRACTThe anti-influenza drug oseltamivir is an ester prodrug activated by hepatic carboxylesterases. Plasma esterases also convert up to 31.8% of the parent compound to the active metabolite after 4 h ex vivo, with wide interindividual variation. This source of error is removed by adding the esterase inhibitor dichlorvos to blood collection tubes.

Artemisinin-based combination therapies (ACTs) have contributed substantially to the global decline in Plasmodium falciparummorbidity and mortality, but resistance to artemisinins and their partner drugs is increasing in Southeast Asia, threatening malaria control. New antimalarial compounds will not be generally available soon.

Although published data on the safety and effectiveness of castor oil for the induction of labor are sparse, it is widely used for this purpose outside of medical settings, especially by American nurse-midwives. Its low cost, easy storage, and apparent safety contribute to its popularity. The results of 4 small clinical trials evaluating its safety and effectiveness for labor induction were contradictory.

ABSTRACTEx vivo conversion of the anti-influenza drug oseltamivir to its active metabolite can be inhibited by the esterase inhibitor dichlorvos or by using commercial fluoride-oxalate tubes. Oseltamivir and its active metabolite remain intact in plasma samples during a proposed virus heat inactivation step: incubation at 60°C for 45 min.

ABSTRACTThe gametocidal activities of chloroquine and artesunate were compared. The relative risk (RR) of having detectable gametocytes appear after treatment initiation was lower in artesunate-treated patients (n= 792) than in chloroquine-treated patients (n= 695) (RR = 0.29; 95% CI = 0.2 to 0.40; P< 0.0001). The duration and magnitude of gametocyte carriage were also lower for artesunate than chloroquine. By reducing the transmission of Plasmodium vivaxto the vector, artesunate could therefore reduce the incidence of P. vivaxmalaria.