Age, Weight, and CYP2D6 Genotype Are Major Determinants of Primaquine Pharmacokinetics in African Children

Abstract

Low-dose primaquine is recommended to prevent Plasmodium falciparum malaria transmission in areas threatened by artemisinin resistance and areas aiming for malaria elimination. Community treatment campaigns with artemisinin-based combination therapy in combination with the gametocytocidal primaquine dose target all age groups, but no studies thus far have assessed the pharmacokinetics of this gametocytocidal drug in African children. We recruited 40 children participating in a primaquine efficacy trial in Burkina Faso to study primaquine pharmacokinetics. These children received artemether-lumefantrine and either a 0.25- or a 0.40-mg/kg primaquine dose. Seven blood samples were collected from each participant for primaquine and carboxy-primaquine plasma levels determinations: one sample was collected before primaquine administration and six after primaquine administration according to partially overlapping sampling schedules. Physiological population pharmacokinetic modeling was used to assess the impact of weight, age, and CYP2D6 genotype on primaquine and carboxy-primaquine pharmacokinetics. Despite linear weight normalized dosing, the areas under the plasma concentration-time curves and the peak concentrations for both primaquine and carboxy-primaquine increased with age and body weight. Children who were CYP2D6 poor metabolizers had higher levels of the parent compound, indicating a lower primaquine CYP2D6-mediated metabolism. Our data indicate that primaquine and carboxy-primaquine pharmacokinetics are influenced by age, weight, and CYP2D6 genotype and suggest that dosing strategies may have to be reconsidered to maximize the transmission-blocking properties of primaquine. (This study has been registered at ClinicalTrials.gov under registration no. NCT01935882.)

Enantiospecific pharmacokinetics and drug–drug interactions of primaquine and blood-stage antimalarial drugs

“…Including pre-systemic metabolism of primaquine in the model improved the model fit significantly, consistent with a recent published pharmacokinetic study. 35 …”

“…Clearance and volume parameters were allometrically scaled by body weight, which has also been described in previously published pharmacokinetic models of primaquine. 32 , 35 …”

Enantiospecific Pharmacogenomics of Fluvastatin

“…Triallelic rs12367888 genotype calling was verified and missing data supplemented by Sanger sequencing. All participants were genotyped for relevant CYP2D6 alleles with TaqMan genotyping assays . The CYP2D6 copy number was determined with a TaqMan copy number assay targeting exon 9.…”

“…All participants were genotyped for relevant CYP2D6 alleles with TaqMan genotyping assays. 44 The CYP2D6 copy number was determined with a TaqMan copy number assay targeting exon 9. CYP2D6 metabolizer status was inferred from the genotypes using the activity score method.…”

Understanding human genetic factors influencing primaquine safety and efficacy to guide primaquine roll-out in a pre-elimination setting in southern Africa

“…The PMs with the CYP2D6*4 polymorphism are associated with PQ treatment failure in P. vivax [ 24 ], whereas IMs harbouring CYP2D6*17 mutations have been linked with diminished enzyme activity in black Africans [ 25 ]. Whilst the impact of CYP2D6 metabolizer status on the efficacy of single low-dose PQ for gametocyte clearance is currently unknown, it is conceivable that the gametocytocidal effect of PQ would be reduced if lower plasma concentrations of the active PQ metabolite are achieved [ 26 ].…”