Abstract
The study aimed to characterize the population pharmacokinetics of amodiaquine (AQ) and its major metabolite N-desethylamodiaquine (N-DEAQ), and to assess the correlation between exposure to N-DEAQ and treatment outcome. Blood samples from children in two studies in Zanzibar and one in Papua New Guinea were included in the pharmacokinetic analysis (n = 86). The children had been treated with AQ in combination with artesunate or sulphadoxine-pyrimethamine. The population pharmacokinetics of AQ and N-DEAQ were modeled using the non-linear mixed effects approach as implemented in NONMEM. Bayesian post-hoc estimates of individual pharmacokinetic parameters were used to generate individual profiles of N-DEAQ exposure. The correlation between N-DEAQ exposure and effect was studied in 212 patients and modeled with logistic regression in NONMEM. The pharmacokinetics of AQ and N-DEAQ were best described by two parallel two-compartment models with a central and a peripheral compartment for each compound. The systemic exposure to AQ was low in comparison to N-DEAQ. The t 1/2λ of N-DEAQ ranged from 3 days to 12 days. There was a statistically significant, yet weak, association between N-DEAQ concentration on day 7 and treatment outcome. The age-based dosing schedule currently recommended in Zanzibar appeared to result in inadequate exposure to N-DEAQ in many patients.
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Murphy SC and Breman JG (2001). Gaps in the childhood malaria burden in Africa: cerebral malaria, neurological sequelae, anemia, respiratory distress, hypoglycemia and complications of pregnancy. Am J Trop Med Hyg 64(1–2 Suppl): 57–67
Li XQ, Bjorkman A, Andersson TB, Ridderstrom M and Masimirembwa CM (2002). Amodiaquine clearance and its metabolism to N-desethylamodiaquine is mediated by CYP2C8: a new high affinity and turnover enzyme-specific probe substrate. J Pharmacol Exp Ther 300(2): 399–407
Pussard E, Verdier F, Faurisson F, Scherrmann JM, Le Bras J and Blayo MC (1987). Disposition of monodesethylamodiaquine after a single oral dose of amodiaquine and three regimens for prophylaxis against Plasmodium falciparum malaria. Eur J Clin Pharmacol 33(4): 409–414
Winstanley P, Edwards G, Orme M and Breckenridge A (1987). The disposition of amodiaquine in man after oral administration. Br J Clin Pharmacol 23(1): 1–7
Winstanley PA, Simooya O, Kofi-Ekue JM, Walker O, Salako LA, Edwards G, Orme ML and Breckenridge AM (1990). The disposition of amodiaquine in Zambians and Nigerians with malaria. Br J Clin Pharmacol 29(6): 695–701
White NJ, Looareesuwan S, Edwards G, Phillips RE, Karbwang J, Nicholl DD, Bunch C and Warrell DA (1987). Pharmacokinetics of intravenous amodiaquine. Br J Clin Pharmacol 23(2): 127–135
Laurent F, Saivin S, Chretien P, Magnaval JF, Peyron F, Sqalli A, Tufenkji AE, Coulais Y, Baba H and Campistron G (1993). Pharmacokinetic and pharmacodynamic study of amodiaquine and its two metabolites after a single oral dose in human volunteers. Arzneimittelforschung 43(5): 612–616
Gerstner U, Prajakwong S, Wiedermann G, Sirichaisinthop J, Wernsdorfer G and Wernsdorfer WH (2003). Comparison of the in-vitro activity of amodiaquine and its main metabolite, monodesethyl-amodiaquine, in Plasmodium falciparum. Wien Klin Wochenschr 115(Suppl 3): 33–38
Childs GE, Boudreau EF, Milhous WK, Wimonwattratee T, Pooyindee N, Pang L and Davidson DE (1989). A comparison of the in vitro activities of amodiaquine and desethylamodiaquine against isolates of Plasmodium falciparum. Am J Trop Med Hyg 40(1): 7–11
Mariga ST, Gil JP, Sisowath C, Wernsdorfer WH and Bjorkman A (2004). Synergism between amodiaquine and its major metabolite, desethylamodiaquine, against Plasmodium falciparum in vitro. Antimicrob Agents Chemother 48(11): 4089–4096
Aubouy A, Bakary M, Keundjian A, Mbomat B, Makita JR, Migot-Nabias F, Cot M, Le Bras J and Deloron P (2003). Combination of drug level measurement and parasite genotyping data for improved assessment of amodiaquine and sulfadoxine-pyrimethamine efficacies in treating Plasmodium falciparum malaria in Gabonese children. Antimicrob Agents Chemother 47(1): 231–237
Hombhanje FW, Hwaihwanje I, Tsukahara T, Saruwatari J, Nakagawa M, Osawa H, Paniu MM, Takahashi N, Lum JK, Aumora B, Masta A, Sapuri M, Kobayakawa T, Kaneko A and Ishizaki T (2005). The disposition of oral amodiaquine in Papua New Guinean children with falciparum malaria. Br J Clin Pharmacol 59(3): 298–301
Lindegårdh N, Forslund M, Green MD, Kaneko A and Bergqvist Y (2002). Automated solid-phase extraction for determination of amodiaquine, chloroquine and metabolites in Capillary blood on sampling paper by liquid chromatography. Chromatographia 55: 5–12
Jonsson EN and Karlsson MO (1999). Xpose—an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 58(1): 51–64
Beal SL and Sheiner LB (1982). Estimating population kinetics. Crit Rev Biomed Eng 8(3): 195–222
Wahlby U, Jonsson EN and Karlsson MO (2001). Assessment of actual significance levels for covariate effects in NONMEM. J Pharmacokinet Pharmacodyn 28(3): 231–252
Gobburu JV and Lawrence J (2002). Application of resampling techniques to estimate exact significance levels for covariate selection during nonlinear mixed effects model building: some inferences. Pharm Res 19(1): 92–98
Holford N (2005) A degenerative predictive check. In: 14th P.A.G.E. Meeting. Pamplona
Montgomery DC, Peck EA and Vining GG (2001). Introduction to linear regression analysis. Wiley, Chichester, New York
Holford N (2007) Wings for NONMEM Version 600. Accessed: April 2007
Mihaly GW, Nicholl DD, Edwards G, Ward SA, Orme ML, Warrell DA and Breckenridge AM (1985). High-performance liquid chromatographic analysis of amodiaquine in human plasma. J Chromatogr 337(1): 166–171
Wennerholm A, Nordmark A, Pihlsgard M, Mahindi M, Bertilsson L and Gustafsson LL (2006). Amodiaquine, its desethylated metabolite, or both, inhibit the metabolism of debrisoquine (CYP2D6) and losartan (CYP2C9) in vivo. Eur J Clin Pharmacol 62(7): 539–546
Rowland M and Tozer TN (1995). Clinical pharmacokinetics: concepts and applications. Williams and Wilkins, USA
Guidelines for the treatment of malaria/ World Health Organization 2006
Taylor WR, Terlouw DJ, Olliaro PL, White NJ, Brasseur P and ter Kuile FO (2006). Use of weight-for-age-data to optimize tablet strength and dosing regimens for a new fixed-dose artesunate-amodiaquine combination for treating falciparum malaria. Bull World Health Organ 84(12): 956–964
Martensson A, Stromberg J, Sisowath C, Msellem MI, Gil JP, Montgomery SM, Olliaro P, Ali AS and Bjorkman A (2005). Efficacy of artesunate plus amodiaquine versus that of artemether-lumefantrine for the treatment of uncomplicated childhood Plasmodium falciparum malaria in Zanzibar, Tanzania. Clin Infect Dis 41(8): 1079–1086
Bukirwa H, Yeka A, Kamya MR, Talisuna A, Banek K, Bakyaita N, Rwakimari JB, Rosenthal PJ, Wabwire-Mangen F, Dorsey G and Staedke SG (2006). Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda. PLoS Clin Trials 1(1): e7
Eggelte TA, Agtmael MA and Boxtel CJ (1999). Artemisinin drugs in the treatment of malaria: from medicinal herb to registered medication. Trends Pharmacol Sci 20(5): 199–205
Taylor WR, Rigal J and Olliaro PL (2003). Drug resistant falciparum malaria and the use of artesunate-based combinations: focus on clinical trials sponsored by TDR. J Vector Borne Dis 40(3–4): 65–72
Borrmann S, Adegnika AA, Missinou MA, Binder RK, Issifou S, Schindler A, Matsiegui PB, Kun JF, Krishna S, Lell B and Kremsner PG (2003). Short-course artesunate treatment of uncomplicated Plasmodium falciparum malaria in Gabon. Antimicrob Agents Chemother 47(3): 901–904
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Hietala, S.F., Bhattarai, A., Msellem, M. et al. Population pharmacokinetics of amodiaquine and desethylamodiaquine in pediatric patients with uncomplicated falciparum malaria. J Pharmacokinet Pharmacodyn 34, 669–686 (2007). https://doi.org/10.1007/s10928-007-9064-2
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DOI: https://doi.org/10.1007/s10928-007-9064-2