, Kyle John Wilby2 and Mary H. H. Ensom1
(1)
Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, Canada
(2)
College of Pharmacy, Qatar University, Doha, Qatar
This chapter provides details of studies that describe drug interactions in which antimalarial drugs affect the pharmacokinetics of various co-administered (non-antimalarial) drugs. These antimalarials include amodiaquine, artemether, artemisinin, artesunate, atovaquone, chloroquine, mefloquine, proguanil, and quinine.
5.1 Effects of Amodiaquine on the Pharmacokinetics of Drugs
In order characterize the effects of amodiaquine on CYP450-mediated metabolism in humans, Wennerholm et al. (2006) administered a single dose of amodiaquine (600 mg) in the presence or absence of a single oral dose of a cocktail of CYP450-selective probe substrates: 10 mg debrisoquine (CYP2D6), 20 mg omeprazole (CYP219), 25 mg losartan (CYP2C9), and 100 mg caffeine (CYP1A2) to 12 healthy Swedish subjects who were determined, via genotyping, to be wild-type metabolizers, using a prospective, cross over design where each subject served as their own control. The primary endpoint was the effect of amodiaquine on the metabolic ratios between each probe substrate and a selected metabolite (i.e. debrisoquine/4-hydroxydebrisoquine). However, the typical pharmacokinetic parameters (i.e. AUC, Cmax, t1/2, etc.) were not reported in the study, limiting further mechanistic interpretation of the data. The major finding from the study was that amodiaquine significantly elevated the metabolic ratios for debrisoquine (CYP2D6) and losartan (CYP2C9) by 1.4 and 1.7 fold, respectively, but had little effect on omeprazole and caffeine metabolism. The effects were reversible upon further washout and re-administration of probe substrates alone, supporting the validity of the interaction. The effects of amodiaquine on debrisoquine metabolism in this study is supported by the in vitro finding from Bapiro et al. (2001) where amodiaquine was shown to be a strong inhibitor of CYP2D6 activity. Likewise, the lack of effects of amodiaquine on omeprazole and caffeine metabolism is also consistent with its weak inhibitory effects toward their respective isoenzymes (i.e. CYP2C19 and CYP1A2 respectively) in vitro. On the other hand, amodiaquine was shown to be a weak inhibitor, in vitro, of CYP2C9, but had a significant effect on losartan metabolism in this study. The discrepancy, which remains to be clarified, may be due to an effect on alternative metabolic pathways not yet studied for amodiaquine and losartan, or simply the inability to extrapolate in vitro to in vivo findings. A few limitations should be considered while interpreting the findings from this study: although the authors suggested that these effects may be due to amodiaquine and/or its major metabolite N-desethylamodiaquine, the study was actually not designed to determine the relative contribution of either the parent or metabolite toward enzyme inhibition. Also, the dose of amodiaquine used (i.e. 600 mg orally × 1) is not reflective of the typical clinical approach, where a much higher dose is given at steady-state conditions. The inhibitory effects of amodiaquine may very well be different in these different settings, in the true target population, which remains to be studied (Table 5.1).
Table 5.1
Effects of antimalarial drugs on pharmacokinetics of co-administered drugs
Antimalarial | Population | Design | n | Effect drug dosing | Antimalarial dosing | Effects of antimalarials on PK of drugs | Reference | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Analyte | AUC | Cmax | Cmin | Tmax | Vd/F | CL/F | t1/2 | |||||||
Amodiaquine | Healthy (Swedish Caucasian, 9 M) Age: 33 years (mean) | Open label Prospective Cross over | 12 | 600 mg × 1 orally | Caffeine (100 mg) Debrisoquine (10 mg) Omeprazole (20 mg) Losartan (25 mg) | Caffeine Debrisoquine Omeprazole Losartan (cocktail) | ND (see text) | ND | ND | ND | ND | ND | ND | Wennerholm et al. (2006) |
Artemether | Healthy volunteers | Open label Prospective Cross over | 15 | Cocktail of caffeine (100 mg), coumarin (5 mg), midazolam (7.5 mg), mephenytoin (100 mg), metoprolol (100 mg), and chlorzoxazone (250 mg) on days 1 and 5 | 100 mg orally once daily for 5 days | Caffeine/coumarin/midazolam/mephenytoin/metoprolol/chlorzoxazone | ND (see text) | ND | ND | ND | ND | ND | ND | Asimus et al. (2007) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | R-omeprazole (after 1 dose of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | R-omeprazole (after 7 doses of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | R-omeprazole (after 14 doses of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | S-omeprazole (after 1 dose of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | S-omeprazole (after 7 doses of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | S-omeprazole (after 14 doses of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | R-5 hydroxyomeprazole (after 1 dose of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | R-5 hydroxyomeprazole (after 1 dose of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | R-5 hydroxyomeprazole (after 1 dose of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | S-5 hydroxyomeprazole (after 1 dose of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | S-5 hydroxyomeprazole (after 1 dose of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy male Vietnamese subjects | Open label Prospective Cross over | 9 (8 extensive metabolizers) | 20 mg omeprazole orally × 1 | 500 mg orally daily × 7 days | S-5 hydroxyomeprazole (after 1 dose of artemisinin) | ND (did not compared to omeprazole only control—see text) | ND | ND | ND | ND | ND | ND | Mihara et al. (1999) |
Artemisinin | Healthy volunteers (6 M) Age: 36–54 years old | Open label Prospective Cross over | 10 | 136.5 mg orally × 1 | 500 mg orally × 1 | Caffeine | ↔ | ↔ | ND | ↔ | ND | ↔ | ↔ | Bapiro et al. (2005) |
Artemisinin | Healthy volunteers | Open label Prospective Cross over | 15 | Cocktail of caffeine (100 mg), coumarin (5 mg), midazolam (7.5 mg), mephenytoin (100 mg), metoprolol (100 mg), and chlorzoxazone (250 mg) on days 1 and 5 | 500 mg orally once daily for 5 days | Caffeine/coumarin/midazolam/mephenytoin/metoprolol/chlorzoxazone | ND (see text) | ND | ND | ND | ND | ND | ND | Asimus et al. (2007) |
Dihydroartemisinin | Healthy volunteers | Open label Prospective Cross over | 14 | Cocktail of caffeine (100 mg), coumarin (5 mg), midazolam (7.5 mg), mephenytoin (100 mg), metoprolol (100 mg), and chlorzoxazone (250 mg) on days 1 and 5 | 60 mg orally once daily for 5 days | Caffeine/coumarin/midazolam/mephenytoin/metoprolol/chlorzoxazone | ND (see text) | ND | ND | ND | ND | ND | ND | Asimus et al. (2007) |
Artemisinin | Healthy male Vietnamese subjects Age: 32 years (avg) Wt: 58 kg | Open label Prospective Randomized Cross over | 12 | 200 mg orally × 1 | 500 mg orally daily for 5 days | Coumarin (hydroxycoumarin) | ↔ | ND | ND | ND | ND | ND | ND | Asimus et al. (2007) |
Artemisinin | Healthy male Vietnamese subjects Age: 32 years (avg) Wt: 58 kg | Open label Prospective Randomized Cross over | 12 | 200 mg orally × 1 | 500 mg orally daily for 5 days | Coumarin (hydroxycoumarin glucuronide) | ↑(26 %) | ND | ND | ND | ND | ND | ND | Asimus et al. (2008) |
Artemisinin | Healthy male Vietnamese subjects Age: 32 years (avg) Wt: 58 kg | Open label Prospective Randomized Cross over | 12 | 4 mg piece of gum orally × 1 | 500 mg orally daily for 5 days | Nicotine | ↓(46 %) | ND | ND | ND | ND | ND | ND | Asimus et al. (2008) |
Artemisinin | Healthy male Vietnamese subjects Age: 32 years (avg) Wt: 58 kg | Open label Prospective Randomized Cross over | 12 | 4 mg piece of gum orally × 1 | 500 mg orally daily for 5 days | Nicotine (Cotinine) | ↓(8 %) | ND | ND | ND | ND | ND | ND | Asimus et al. (2008) |
Artesunate | Healthy volunteers | Open label Prospective Cross over | 15 | Cocktail of caffeine (100 mg), coumarin (5 mg), midazolam (7.5 mg), mephenytoin (100 mg), metoprolol (100 mg), and chlorzoxazone (250 mg) on days 1 and 5 | 100 mg orally once daily for 5 days | Caffeine/coumarin/midazolam/mephenytoin/metoprolol/chlorzoxazone | ND (see text) | ND | ND | ND | ND | ND | ND | Asimus et al. (2007) |
Atovaquone | Healthy (all M) Age: 24 years (median) Wt: 70 kg (median) | Open label Prospective Randomized Cross over | 12 | 1,000 mg × 2 orally | 600 mg × 1 orally | Phenytoin | ↔ | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Davis et al. (1996) |
Atovaquone | HIV-infected (5 M) Age: 31 years (median) | Open label Prospective Cross over | 6 | 160/800 mg orally every 12 ours × 1 week | 500 mg orally daily (with food) × 2 weeks | Trimethoprim-sulfamethoxazole | ND (see text) | ND | ND | ND | ND | ND | ND | Falloon et al. (1999) |
Chloroquine | Healthy (all M) Age: 23.4 ± 3.7 years Wt: 72.7 ± 7.2 kg None poor metabolizers | Open label Prospective Cross over | 14 | Cocktail of caffeine (100 mg), mephenytoin (100 mg), debrisoquine (10 mg), chlorzoxazone (250 mg), and dapsone (100 mg) | 250 mg orally daily × 1 and 7 days | Caffeine | ND (see text) | ND | ND | ND | ND | ND | ND | Adedoyin et al. (1998a |
Chloroquine | Healthy (all M) Age: 23.4 ± 3.7 years Wt: 72.7 ± 7.2 kg None poor metabolizers | Open label Prospective Cross over | 14 | Cocktail of caffeine (100 mg), mephenytoin (100 mg), debrisoquine (10 mg), chlorzoxazone (250 mg), and dapsone (100 mg) | 250 mg orally daily × 1 and 7 days | Mephenytoin | ND (see text) | ND | ND | ND | ND | ND | ND | Adedoyin et al. (1998a) |
Chloroquine | Healthy (all M) Age: 23.4 ± 3.7 years Wt: 72.7 ± 7.2 kg None poor metabolizers | Open label Prospective Cross over | 14 | Cocktail of caffeine (100 mg), mephenytoin (100 mg), debrisoquine (10 mg), chlorzoxazone (250 mg), and dapsone (100 mg) | 250 mg orally daily × 1 and 7 days | debrisoquine | ND (see text) | ND | ND | ND | ND | ND | ND | Adedoyin et al. (1998a) |
Chloroquine | Healthy (all M) Age: 23.4 ± 3.7 years Wt: 72.7 ± 7.2 kg None poor metabolizers | Open label Prospective Cross over | 14 | Cocktail of caffeine (100 mg), mephenytoin (100 mg), debrisoquine (10 mg), chlorzoxazone (250 mg), and dapsone (100 mg) | 250 mg orally daily × 1 and 7 days | chlorzoxazone | ND (see text) | ND | ND | ND | ND | ND | ND | Adedoyin et al. (1998a) |
Chloroquine | Heatlhy (Zambians, all M) Age: 21–29 years | Open label Prospective Cross over | 10 | 10 mg orally × 1 | 1,500 mg orally × 1 | Debrisoquine | ND (see text) | ND | ND | ND | ND | ND | ND | Simooya et al. (1998) |
Chloroquine | Healthy (Zambians, all M) Age: 27 ± 4 years Wt. 60.8 ± 5.6 kg | Open label Prospective Cross over | 11 | Not specified | 500 mg orally × 1 (prophylaxis dose) | Debrisoquine | ND (see text) | ND | ND | ND | ND | ND | ND | Masimirembwa et al. (1996) |
Chloroquine | Healthy (Swedish) Age: 38 ± 8 years Wt: 70.2 ± 13 kg | Open label Prospective Cross over | 12 | Not specified | 500 mg orally Q8H × 3 | Debrisoquine | ND (see text) | ND | ND | ND | ND | ND | ND | Masimirembwa et al. (1996) |
Chloroquine | Healthy (Zambians, all M) Age: 27 ± 4 years Wt. 60.8 ± 5.6 kg | Open label Prospective Cross over | 11 | Not specified | 500 mg orally × 1 (prophylaxis dose) | S-Mephentyoin | ND (see text) | ND | ND | ND | ND | ND | ND | Masimirembwa et al. (1996) |
Chloroquine | Healthy (Swedish) Age: 38 ± 8 years Wt: 70.2 ± 13 kg | Open label Prospective Cross over | 12 | Not specified | 500 mg orally Q8H × 3 | S-Mephentyoin | ND (see text) | ND | ND | ND | ND | ND | ND | Masimirembwa et al. (1996) |
Chloroquine | Healthy (all M) Age: 23 years (mean) Wt: 58 kg (mean) | Open label Prospective Cross over | 7 | 1,000 mg orally × 1 | 1,000 mg orally × 1 | Ampicillin | ND (see text) | ND | ND | ND | ND | ND | ND | Ali (1985) |
Chloroquine | Schizophrenic patients Age: 18–40 years old | Open label Prospective Cross over | 5 | Steady-state dosing (400 mg or 500 mg orally daily) | 400 mg orally × 1 | Chlorpromazine | ND (see text) | ND | ND | ND | ND | ND | ND | Makanjuola et al. (1988) |
Chloroquine | Healthy volunteers Age: 23–28 years old Wt: 55–65 kg | Open label Prospective Randomized Cross over | 6 | 50 mg orally × 1 | 300 mg orally × 1 | Imipramine | ND | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Onyeji et al. (1993) |
Chloroquine | Healthy volunteers (all M) Age: 19–31 years old | Open label Prospective Cross over | 5 | 500 mg orally × 1 | 600 mg orally × 1 | Ciprofloxacin | ↓(43 %) | ↓(18 %) | ND | ↔ | ND | ND | ND | Ilo et al. (2006) |
Chloroquine | Healthy volunteers (19 M) Age: 19.3 years (mean) Wt: 89.5 kg (mean) | Open label Prospective Cross over | 24 | 1 g orally daily × 3 days | 1 g orally × 2 days, then 500 mg orally × 1 day | Azithromycin | ↔ | ↔ | ND | ND | ND | ND | ↔ | Cook et al. (2006) |
Chloroquine
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