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International audience; The major human cytochrome P450 CYP2D6 isoform enzyme plays important roles in the liver and in the brain with regards to xenobiotic metabolism. Xenobiotics as CYP2D6 substrates include a whole range of pharmaceuticals, pesticides and plant alkaloids to cite but a few. In addition, a number of endogenous compounds have been shown to be substrates of CYP2D6 including trace amines in the brain such as tyramine and 5-methoxytryptamine as well as anandamide and progesterone. Because of the polymorphic nature of CYP2D6, considerable inter-phenotypic and inter-ethnic differences in the pharmaco/toxicokinetics (PK/TK) and metabolism of CYP2D6 substrates exist with potential consequences on the pharmacology and toxicity of chemicals. Here, large extensive literature searches have been performed to collect PK data from published human studies for a wide range of pharmaceutical probe substrates and investigate human variability in CYP2D6 metabolism. The computed kinetic parameters resulted in the largest open source database, quantifying inter-phenotypic differences for the kinetics of CYP2D6 probe substrates in Caucasian and Asian populations, to date. The database is available in supplementary material (CYPD6 DB) and EFSA knowledge junction (DOI to added). Subsequently, meta-analyses using a hierarchical Bayesian model for markers of chronic oral exposure (oral clearance, area under the plasma concentration time curve) and acute oral exposure (maximum plasma concentration (Cmax) provided estimates of inter-phenotypic differences and CYP2D6-related uncertainty factors (UFs) for chemical risk assessment in Caucasian and Asian populations classified as ultra-rapid (UM), extensive (EMs), intermediate (IMs) and poor metabolisers (PMs). The model allowed the integration of inter-individual (i.e. inter-phenotypic and inter-ethnic), inter-compound and inter-study variability together with uncertainty in each PK parameter. Key findings include 1. Higher frequencies of PMs in Caucasian populations compared to Asian populations (>8% vs 1-2%) for which EM and IM were the most frequent phenotype. 2. Large inter-phenotypic differences in PK parameters for Caucasian EMs (coefficients of variation (CV) > 50%) compared with Caucasian PMs and Asian EMs and IMs (i.e CV < 40%). 3. Inter-phenotypic PK differences between EMs and PMs in Caucasian populations increase with the quantitative contribution of CYP2D6 for the metabolism (fm) for a range of substrates (fm CYP2D6 range: 20-95% of dose) (range: 1-54) to a much larger extent than those for Asian populations (range: 1-4). 4. Exponential meta-regressions between Fm CYP2D6 in EMs and inter-phenotypic differences were also shown to differ between Caucasian and Asian populations as well as CYP2D6-related UFs. Finally, implications of these results for the risk assessment of food chemicals and emerging designer drugs of public health concern, as CYP2D6 substrates, are highlighted and include the integration of in vitro metabolism data and CYP2D6 variability distributions for the development of quantitative in vitro in vivo extrapolation models.

Background In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Methods Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15–0.4 mg PQ base/kg for children aged 1–5 years and 0.15–0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6–11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box–Cox transformation power exponential and tested PQ doses of 1–15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results From the Box–Cox transformation power exponential model, five age categories were selected: (i) 6–11 months (n = 39,886, 6.03%), (ii) 1–5 years (n = 261,036, 45.46%), (iii) 6–9 years (n = 20,770, 3.14%), (iv) 10–14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12–0.25), (ii) 0.21 (0.13–0.37), (iii) 0.25 (0.16–0.38), (iv) 0.26 (0.15–0.38) and (v) 0.27 (0.17–0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244,537/261,036), 99.6 (20,690/20,770), 99.4 (12,086/12,155) and 99.8% (327,620/328,132), respectively. Conclusions We plan to test the safety of this age-based dosing regimen in a large randomised placebo-controlled trial (ISRCTN11594437) of uncomplicated falciparum malaria in G6PDd African children aged 0.5 − 11 years. If the regimen is safe and demonstrates adequate pharmacokinetics, it should be used to support malaria elimination. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0990-6) contains supplementary material, which is available to authorized users.