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Background and Objectives: A high inter-individual variability in the pharmacokinetics of lamotrigine has been observed. Lamotrigine is primarily metabolized by UGT1A4 and UGT2B7, both of which show genetic polymorphisms. Both genetic and non-genetic factors may influence the pharmacokinetics of lamotrigine. The aim of this study was to determine the pharmacokinetic parameters of lamotrigine and to investigate the effect of genetic variants of UGT1A4 and UGT2B7 and various non-genetic factors on its pharmacokinetics., Methods: Four single nucleotide polymorphisms (SNPs; UGT1A4 142 T>G, UGT1A4 70C>T, UGT2B7 372A>G, UGT2B7 -161C>T) were identified using the TaqMan Allelic Discrimination Assay. Data were analyzed using NONMEM. Model evaluation was performed using the bootstrap approach and predictive check., Results: A total of 116 samples were obtained from 75 patients and included in the population analysis. The use of enzyme inducers, valproic acid, and the UGT2B7-161 C>T SNP were found to significantly influence lamotrigine apparent clearance (CL/F). Lamotrigine CL/F in patients carrying the UGT2B7 -161 CT or TT SNP was 18% lower than that in patients carrying the UGT2B7 -161 CC SNP., Conclusion: Both genetic and non-genetic factors were found to influence lamotrigine pharmacokinetics. These factors should be considered when determining lamotrigine dosing. The model presented here could be useful for lamotrigine dose adjustment in clinical practice.

Objective: To investigate the pharmacokinetics, safety and efficacy of the recommended 3-day treatment regimen of Malarone in third-trimester pregnant women with acute uncomplicated falciparum malaria., Methods: Twenty-six pregnant women in their third trimester (gestational age: 24-34 weeks) with acute uncomplicated Plasmodium falciparum malaria who fulfilled the enrollment criteria were recruited from the antenatal clinics of Mae Sot Hospital, Tak Province, Thailand, (n = 8) and the Tropical Diseases Research Centre, Ndola, Zambia (n = 18). Patients were treated with four Malarone tablets (GlaxoSmithKline: each tablet contains 250 mg atovaquone and 100 mg proguanil) once daily for 3 consecutive days. Blood samples were taken for pharmacokinetic investigations of atovaquone, proguanil, and cycloguanil up to 288 h (day 14) after the last dose. Urine samples were collected for the evaluation of proguanil and cycloguanil 0-8, 8-16, 16-24 and 24-48 h after the last dose. Efficacy assessments included the clinical and parasitological evaluation of mothers and newborns. Adverse events were evaluated at each visit to the antenatal clinics., Results: Malarone appeared to be effective and well tolerated when used for the treatment of falciparum malaria in pregnant women. All patients showed prompt clinical improvement and the disappearance of parasitaemia after treatment. There were no serious adverse effects or unexpected adverse effects and no stillbirths or spontaneous abortions. The plasma concentration-time profiles of atovaquone and proguanil in most cases were best characterised by the two-compartment open model with zero-order input with/without absorption lag time and first-order elimination. There were no significant differences in any of the pharmacokinetic parameters of atovaquone, proguanil or cycloguanil between patients from Thailand and Zambia. For atovaquone, a Cmax of 1.33-8.33 microg/ml was reached at 2.0-9.3 h after the last dose on day 2. V/F, CL/F and t(1/2beta) were 6.9-39.5 l/kg, 83-384 ml/h/kg, and 57.8-130.8 h, respectively. The Cmax and t(max) values for proguanil versus cycloguanil were 383-918 versus 0-129 ng/ml and 3.3-8.6 versus 3-12 h, respectively. V/F, CL/F, and t(1/2beta) values for proguanil were 10.7-34.0 l/kg, 431-1,662 ml/h/kg and 11.2-30.3 h. The CL(R-CG), t(1/2z), (CG), proguanil/cycloguanil metabolic ratios, AUC ratios for proguanil to cycloguanil (AUC(PG/CG)) were 107.2-1,001 ml/h/kg, 5-95 ml/h/kg, 7.8-20.7 h, 5-57, and 4.7-20.2, respectively., Conclusion: The pharmacokinetics of atovaquone and cycloguanil appeared to be influenced by the pregnancy status, resulting in an decrease in the Cmax and AUC of approximately twofold.

Objective: To determine the effects of late pregnancy and also oestrogen supplementation on the CYP2C19-mediated biotransformation of proguanil (PG) to its active antifol triazine metabolite cycloguanil (CG)., Methods: Case control study conducted on the NW border of Thailand; a single dose of PG (4 mg/kg) was administered to Karen women in late pregnancy and a single blood and urine sample taken 6 h later. Women were studied in late pregnancy (>36 weeks) and restudied 2 months after delivery. A separate cohort of Karen women newly attending a birth-control clinic were studied before and 3 weeks into their first course of oral contraceptives (OCP: levonorgestrel 0.15 mg and ethinyloestradiol 0.03 mg). Forty-five pregnant women and forty-two healthy OCP users were studied., Results: The results were similar in both groups; pregnancy and OCP use were both associated with reduced formation of cycloguanil (CG). Impaired PG biotransformation was seen in women with the "extensive metaboliser" phenotype (urine PG/CG ratio <10). CG levels, adjusted for dose, were a median (range) 73% (-59 to 420%) higher following the pregnancy than during the pregnancy in women characterised as extensive metabolisers ( P<0.001). CG levels in women characterised as extensive metabolisers were 34% (-54 to 323%) higher before than while taking the OCP ( P<0.01)., Conclusion: Late pregnancy and OCP use impair biotransformation of the active antimalarial metabolite CG from the parent PG. This may be mediated by oestrogen inhibition of CYP2C19 activity. The dose of PG should be increased by 50% in these groups.

The prevalence of putative poor metaboliser (PM) phenotypes of proguanil oxidation in Caucasian populations is 3-10%. The PM frequency in Oriental populations is unknown. In this study the plasma metabolic ratios of proguanil and dapsone to their principal metabolites cycloguanil and monoacetyldapsone were determined in Thai soldiers receiving antifolate drug combinations for malaria prophylaxis. The distribution ratio of proguanil to cycloguanil (PROG/CYC) was highly skewed with no evidence of bimodality. Assuming subjects with a PROG/CYC ratio greater than 10 are PMs from studies in Caucasians, the incidence of PMs in the soldiers would be 18% (30 of 170). The mean PROG/CYC ratio for PMs in the Thai soldiers was 31.2 +/- 28.9 (n = 30) compared with 25.5 +/- 2.5 (n = 3) in a study of Caucasians. The corresponding values for putative EMs were 5.4 +/- 2.1 (n = 140) and 2.4 +/- 0.2 (n = 134). Similar to other Oriental populations, Thais were found to be predominantly (76%, 173 of 228) rapid acetylators of dapsone.