Treatment regimens for post-kala-azar dermal leishmaniasis (PKDL) are usually extrapolated from those for visceral leishmaniasis (VL), but drug pharmacokinetics (PK) can differ due to disease-specific variations in absorption, distribution, and elimination. This study characterized PK differences in paromomycin and miltefosine between 109 PKDL and 264 VL patients from eastern Africa. VL patients showed 0.55-fold (95%CI: 0.41-0.74) lower capacity for paromomycin saturable reabsorption in renal tubules, and required a 1.44-fold (1.23-1.71) adjustment when relating renal clearance to creatinine-based eGFR. Miltefosine bioavailability in VL patients was lowered by 69% (62-76) at treatment start. Comparing PKDL to VL patients on the same regimen, paromomycin plasma exposures were 0.74-0.87-fold, while miltefosine exposure until the end of treatment day was 1.4-fold. These pronounced PK differences between PKDL and VL patients in eastern Africa highlight the challenges of directly extrapolating dosing regimens from one leishmaniasis presentation to another.
Optimizing nutrient supplementation among pregnant and reproductive age women in Kenya (VIRUTUBISHO)
The pharmacokinetics of abacavir (ABC) in African children living with HIV (CLHIV) weighing < 14 kg and receiving pediatric fixed dose combinations (FDC) according to WHO weight bands dosing are limited. An ABC population pharmacokinetic model was developed to evaluate ABC exposure across different World Health Organization (WHO) weight bands.
METHODS
Children enrolled in the LIVING study in Kenya and Uganda receiving ABC/lamivudine (3TC) dispersible tablets (60/30 mg) according to WHO weight bands. A population approach was used to determine the pharmacokinetic parameters. Monte Carlo simulations were conducted using an in silico population with demographic characteristics associated with African CLHIV. ABC exposures (AUC0–24) of 6.4–50.4 mg h/L were used as targets.
RESULTS
Plasma samples were obtained from 387 children. A 1-compartment model with allometric scaling of clearance (CL/F) and volume of distribution (V/F) according to body weight best characterized the pharmacokinetic data of ABC. The maturation of ABC CL/F was characterized using a sigmoidal Emax model dependent on postnatal age (50% of adult CL/F reached by 0.48 years of age). Exposures to ABC were within the target range for children weighing 6.0–24.9 kg, but children weighing 3–5.9 kg were predicted to be overexposed.
CONCLUSIONS
Lowering the ABC dosage to 30 mg twice daily or 60 mg once daily for children weighing 3–5.9 kg increased the proportion of children within the target and provided comparable exposures. Further clinical study is required to investigate clinical implications and safety of the proposed alternative ABC doses.
To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response.
METHODS
Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults.
RESULTS
Data from 265 patients (59% =12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0–24h 187 (162–203) and 242 (217–328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0–28 517 (464–552) and 524 (456–567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25–28) and 30 (28–32) days, respectively] were comparable to previously observed values in adults.
CONCLUSIONS
Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure–response and exposure–toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.
Seasonal malaria chemoprevention (SMC) has been widely implemented by MSF in the African Sahel. It consists of monthly courses of antimalarial drugs during the high-risk season. A single dose of sulfadoxine-pyrimethamine (SP) and a dose of amodiaquine (AQ) are administered by a health worker, and doses of AQ are administered by caregivers at home on the following two days. Poor adherence to AQ might reduce the protective effectiveness of SMC. In an area of Niger where MSF was concerned about the effectiveness of SMC, we performed a study to describe the population pharmacokinetic (PK) properties of AQ when administered as part of SMC. These data were used to develop models describing adherence to SMC among children participating in a case-control study performed in the same area.
METHODS
A convenience sample of 165 children aged 3-59 months was enrolled in Magaria, Niger, in November 2016. All three doses of SMC were administered at home by nurses, and then blood samples were drawn in six predefined sampling windows over the following six weeks. Drug concentrations were determined using a liquid chromatography tandem mass spectrometry-based assay. Concentration-time data were evaluated simultaneously using nonlinear mixed-effects modelling in the software NONMEM (Icon, Hanover, USA). In the case-control study, one-half (n=297) of cases and their 859 healthy village- and age-matched controls were randomly selected to be analysed for drug concentrations and adherence.
ETHICS
This study was approved by the MSF Ethical Review Board and the Comité Consultatif National d’Éthique of Niger.
RESULTS
We used two-compartment and three-compartment disposition models respectively to describe AQ and desethylamodiaquine (DEAQ) concentration-time profiles. This method for evaluation of adherence showed a sensitivity of 65-71%, when the first dose of SMC was directly observed by a health worker. Among case-control study participants, modelled adherence simulations and measured DEAQ concentrations showed poor adherence. Using the optimal model, only 7% of cases and 8% of controls had complete adherence to AQ. Even when using the most conservative cut-offs in the model (5th percentile of DEAQ concentration), only 10% of cases and 17% of controls had complete adherence.
CONCLUSION
To our knowledge, this is the first description of the population pharmacokinetics of AQ when used in the setting of SMC; the model was robust and showed good predictive performance. Despite community engagement efforts, adherence to SMC was very poor in this setting. Efforts to improve adherence are urgently needed, both to protect children against malaria and to prevent emergence of resistance to SP and AQ.
CONFLICTS OF INTEREST
None declared.