Dihydroartemisinin-piperaquine is an important artemisinin-based antimalarial treatment. This is to date the largest reported pharmacokinetic study of piperaquine conducted in patients with malaria. In the study, a population pharmacokinetic model for piperaquine was established by using NONMEM. The pharmacokinetic properties of piperaquine were characterized by a two-compartment disposition model with first-order absorption. The effective random residual error model should be considered multiplicative, since the modeled data was log transformed. This population pharmacokinetic study shows that there are no significant pharmacokinetic differences for piperaquine between the older, standard four-dose regimen and the newer, simplified three-dose regimen and therefore provides further support for this once-daily treatment regimen to improve treatment adherence and efficacy.
This study concentrated more on characterizing piperaquine disposition, so insufficient data were collected during the absorption phase, which partly explains the uncertainty in the absorption rate constant. The derived population estimates of pharmacokinetic parameters are otherwise generally similar to those previously reported, with a very large steady-state volume of distribution (V
= 874 liter/kg) and a long estimated terminal half-life (t1/2β
) of 28 days (Tables and ). The half-life might still be underestimated, since the sparsely collected data were distributed over a long sampling period with no more than one measured concentration beyond 7 days after starting treatment. Even though the two-compartment model employed under-predicted the highest concentrations as well as those at the last sampling time point, the available data did not support a three-compartment disposition model (Fig. ). The presence of an even longer terminal elimination phase has been suggested (27
). In these respects, piperaquine is similar to chloroquine, which also has an extremely large total apparent volume of distribution and a very long terminal half-life. The terminal half-life is an important determinant of the temporal distribution of recrudescences (and thus the duration of follow-up required in clinical trials), as it determines the posttreatment prophylactic effect and affects the propensity to select for resistance (32
Previous studies have shown a large interindividual random variability of piperaquine kinetics, which was also found in this study (13
). Body weight, centered on the median value, was included in the final model to explain a portion of the interindividual random variability in clearance and in the central volume of distribution. There was an apparent increase in body weight-normalized oral clearance and a minor decrease in body weight-normalized oral steady-state volume of distribution with increasing body weight (Fig. ). Body weight-normalized oral clearance was lower in children than in adults, and the resulting derived terminal half-life showed a marked prolongation in small children. However, the covariate function provided by these data should not be extrapolated beyond the studied population demographics, since for children below 10 kg of body weight parameter estimates will be unreasonable. The pharmacokinetic differences between children and adults observed in this study will need to be confirmed, since a relatively small number of children were studied and there could be model misspecification. However, if these differences are confirmed in larger studies, they might provide some indication of the drug-metabolizing enzymes involved. For example, it has been suggested that the cytochrome P450 (CYP) enzymes CYP1A2 and CYP2B6 are not fully matured until 10 years and 20 years of age, respectively (14
). A retrospective study of 45 drugs also showed that glucuronidation substrates displayed significantly longer half-lives for children (2 to 12 years) and adolescents (12 to 18 years) than for adults (10
). The trend in body weight-normalized clearance versus body weight is similar to that seen for caffeine (i.e., CYP1A2) and diclofenac (i.e., glucuronidation) and would also be reasonable for drugs that are eliminated predominantly by renal filtration (14
). Piperaquine has previously been shown to be eliminated by both metabolism (26
) and renal excretion (28
), but the extent to which each elimination pathway contributes requires further evaluation.
Pharmacokinetics did not explain the reinfections in the study. The plasma concentrations were not different in reinfected patients, and there were no significant differences in the pharmacokinetic parameters compared to the population mean estimates (Fig. ). The reinfected patients showed simulated piperaquine plasma concentrations of between 4 to 13 ng/ml and 1 to 8 ng/ml at the time of presentation with reinfections of P. falciparum and P. vivax, respectively. This is a low transmission setting, so these values must represent concentrations below the in vivo MIC for prevalent parasites. Considering a blood stage incubation period of not less than 7 days (reflecting multiplication rates of ≤10-fold per asexual cycle), the concentrations 1 week before reinfection of P. falciparum emerged were between 5 to 14 ng/ml, which suggests that this is a lower limit for the in vivo MIC in this region. Population mean plasma concentrations of 12 and 13 ng/ml could be seen at day 20 after the initiation of the DP3 and DP4 treatments, respectively. This suggests a mean posttreatment prophylactic effect of approximately 20 days with the current dosage. A simulated distribution of concentrations indicates most patients to be below 10 ng/ml at day 28 (Fig. , inserts). Estimating the MIC for P. vivax is more complex as, unlike P. falciparum reinfections, which may be assumed to be random, the emergence of relapses occurs at approximately 3-week intervals.
Although there were only 11 children in the study, they tended to have a smaller central volume of distribution, a shorter distribution half-life (t1/2α
), and a more rapid fall in early piperaquine plasma concentrations compared to the population mean profile. This finding has potentially important therapeutic consequences for the use of the dihydroartemisinin-piperaquine combination. Thus, even though the initial concentrations of piperaquine were higher and the terminal elimination half-life was longer in children, they had lower plasma concentrations during the putative critical period between 3 and 20 days after starting treatment. The initial therapeutic response is determined almost entirely by the artemisinin derivative, so high early piperaquine levels offer no immediate benefit. However, after the second asexual cycle (>4 days), all the dihydroartemisinin has been eliminated, and parasite clearance depends entirely on the piperaquine partner drug. It is evident that the plasma concentration profiles in these children (Fig. and ) fall close to the putative in vivo MICs in approximately 10 days or less, so children would be expected to be at higher risk of recrudescence and earlier reinfection than the mean population. An increased risk of failure in children has been suggested in recent studies in West Papua (11
). Price et al. (27
) showed plasma concentrations of piperaquine on day 7 to be a major determinant of the therapeutic response to dihydroartemisinin-piperaquine. Plasma piperaquine concentrations below 30 ng/ml on day 7 were associated with a higher failure risk (adjusted hazard ratio = 6.6 [95% confidence interval, 1.9 to 23]; P
= 0.003) and were observed in 38% (21/56) of children less than 15 years of age and in 22% (31/140) of adults (20
). The lower day 7 piperaquine plasma concentrations and the higher failure rates in children are in agreement with the present finding of an altered pharmacokinetic profile. This indicates that the time above MIC or AUC/MIC is important as a pharmacokinetic-pharmacodynamic determinant for slowly eliminated antimalarial drugs and that the total AUC can be a poor predictor of the therapeutic response for drugs with multiphasic disposition kinetics (Fig. ). The piperaquine dose in children might need to be increased, although their tolerance for higher doses of piperaquine needs to be established.
These results are somewhat different from those in a previous study with 47 Cambodian children (2 to 10 years) with malaria, which described a shorter 14-day elimination half-life for children (13
). The differences could result from the relatively small number of children studied here (n
= 11), which could be nonrepresentative, as this compound displays large interindividual variability. Differences between studies might also result from differences in the duration of sampling and/or drug quantification sensitivity. Individual simulations of patients below 30 kg of body weight showed a good agreement between observed and predicted piperaquine concentrations, indicating a reasonably good pharmacokinetic characterization in these children. The lower AUCday 3-20
values in this study are supported by studies in West Papua where day 7 piperaquine concentrations in children were lower than in adults when the subjects were dosed according to kilograms of body weight (11
This study confirms that piperaquine exhibits considerable interindividual pharmacokinetic variability and has a very large apparent volume of distribution and a very slow elimination phase. It suggests that despite having a smaller central volume of distribution and a slower elimination rate than adults, children might have lower piperaquine concentrations in the therapeutically important period immediately following treatment. If this finding is confirmed in other malaria-affected regions, then consideration should be given to increasing the weight-adjusted dosage for children.