Ali Mohamed Ali (1,2,3), Melissa Penny (1,2), Lesley Workman (4,5), Karen I. Barnes (4,5), Paolo Denti (4) on behalf of the WWARN Amodiaquine PKPD study group (5)
(1) University of Basel, Basel, Switzerland. (2) Swiss Tropical and Public Health Institute, Basel, Switzerland. (3) Ifakara Health Institute, Bagamoyo, Tanzania. (4) University of Cape Town, Cape Town, South Africa, (5) Worldwide Antimalarial Resistance Network
Objectives: To characterise the pharmacokinetics of the antimalarial amodiaquine (AQ) and its active metabolite desethylamodiaquine (DEAQ) to a) test whether higher cure rates with the fixed dose combination relate to higher drug exposure and b) inform optimal dosing if exposure is lower in neglected populations (e.g. very young children, pregnant women).
Methods: Pooled analysis of individual patient data from seven clinical trials [1-7] on AQ given as loose or fixed-dose formulation daily for 3 days either alone or in combination with artesunate (AS). Studies were conducted in six countries including both African and Asian populations. The dosage, drug formulation and sampling schedule varied between studies. Concentration-time data were analyzed using NONMEM 7.3 and FOCE-I. The model was developed starting with the most intensely sampled dataset and further data sets added step-by-step, as previously described [8]. Allometric scaling and maturation were used to adjust for differences in body size and age [9]. The effect of disease on PK was tested using an exponential function.
Results: A combined parent (AQ) and metabolite (DEAQ) model was used, with absorption through six transit compartments and a two-compartment disposition for AQ and three-compartment disposition for DEAQ. Patients receiving AS + AQ, either in loose or fixed-dose combination formulations, had higher bioavailability than those receiving AQ alone. Maturation of clearance (based on post-menstrual age) was found to improve the fit. Mature clearance for a 49 kg patient was estimated at 2710 L/h for AQ and 29.4 L/h for DEAQ. Clearance was lower in Thai pregnant women and higher in the patients from the Democratic Republic of Congo. A disease effect was found, with clearance doubling between the initiation of treatment and Day 3 when most symptoms had resolved.
Conclusions: The higher bioavailability of AQ given with AS in a fixed dose combination is consistent with previous reports [10] of higher efficacy of this fixed dose formulation. This study is the first to describe the maturation effect on clearance of AQ and DEAQ. The model can be used to optimize dosing regimens so that infants and younger children receive the same exposure levels as adults. The disease effect found in this study should be better characterized by including studies involving both healthy volunteers and malaria patients.
References:
[1] Adjei, G. O. et al. Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria. Antimicrob. Agents Chemother. 52, 4400–6 (2008)
[2] Mwesigwa, J. et al. Pharmacokinetics of artemether-lumefantrine and artesunate-amodiaquine in children in Kampala, Uganda. Antimicrob. Agents Chemother. 54, 52–9 (2010)
[3] Jullien, V. et al. Population pharmacokinetics and pharmacodynamic considerations of amodiaquine and desethylamodiaquine in Kenyan adults with uncomplicated malaria receiving artesunate-amodiaquine combination therapy. Antimicrob. Agents Chemother. 54, 2611–2617 (2010)
[4] Tarning, J. et al. Population pharmacokinetic and pharmacodynamic modeling of amodiaquine and desethylamodiaquine in women with Plasmodium vivax malaria during and after pregnancy. Antimicrob. Agents Chemother. 56, 5764–73 (2012)
[5] Rijken, M. J. et al. Pharmacokinetics of amodiaquine and desethylamodiaquine in pregnant and postpartum women with Plasmodium vivax malaria. Antimicrob. Agents Chemother. 55, 4338–42 (2011)
[6] Sinoul, V. et al. Pharmacokinetics and pharmacodynamics of a new ACT formulation : ArtesunatelAmodiaquine ( TRIMALAC ~ following oral administration in African malaria patients. 34, 133–142 (2009)
[7] Stepniewska, K. et al. Population pharmacokinetics of artesunate and amodiaquine in African children. Malar. J. 8, 200 (2009)
[8] Svensson, E. et al. Integration of data from multiple sources for simultaneous modelling analysis: Experience from nevirapine population pharmac okinetics. Br. J. Clin. Pharmacol. 74, 465–476 (2012)
[9] Anderson, B. & Holford, N. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu. Rev. Pharmacol. Toxicol. 48, 303–332 (2008)
[10] WorldWide Antimalarial Resistance Network (WWARN) AS-AQ Study Group et al. The effect of dosing strategies on the therapeutic efficacy of artesunate-amodiaquine for uncomplicated malaria: a meta-analysis of individual patient data. BMC Med. 13, 66 (2015)
Reference: PAGE 25 (2016) Abstr 6039 [www.page-meeting.org/?abstract=6039]
Poster: Drug/Disease modeling - Infection