, 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 antimalarial drugs. These antimalarials include amodiaquine, artemether, artemisinin, artesunate, atovaquone, chloroquine, dapsone, mefloquine, primaquine, proguanil, pyrimethamine, quinidine, quinine, sulfadoxine/pyrimethamine, and tafenoquine.
6.1 Effects of Amodiaquine on the Pharmacokinetics of Antimalarials
Omoruyi et al. (2007) studied the effects of amodiaquine on the pharmacokinetics of halofantrine in 10 healthy Nigerian males, using a cross over design with an 8-week washout. Subjects received a single oral dose of 500 mg halofantrine with or without pre-administered amodiaquine, given as a single 600 mg oral dose 1 day prior. The major findings were a lack of any observable or statistical change in the Tmax (6 vs. 7 h), Cmax (144 ± 53 vs. 164 ± 58 μg/L, mean ± SEM), t1/2 (142 ± 23 vs. 139 ± 28), or AUC∞ (14,932 ± 4,932 vs. 17,329 ± 5,988 μg h/L) for halofantrine vs. combined therapy, respectively. Little differences were observed for desbutylhalofantrine, the major metabolite, with respect to Tmax, Cmax, mean residence time, and AUC, when subjects were given halofantrine or in combination with amodiaquine. It has been shown, in vitro, that human CYP3A4 and CYP3A5 are major isoenzymes responsible for the N-debutylation of halofantrine (Baune et al. 1999) and amodiaquine is a weak inhibitor of these enzymes (Bapiro et al. 2001; Baune et al. 1999), supporting the lack of pharmacokinetic interaction observed in this study. However, there was significant variability, which in conjunction with the relatively small and sample size, could have yielded false negative findings. As well, only single doses of halofantrine and amodiaquine were used, which may not reflect the true clinical, steady-state, situation where subjects would be given multiple doses of either agent. Despite the lack of pharmacokinetic interaction, however, the authors did note a prolongation of QT interval in the combination group compared to subjects on halofantrine alone, indicating a pharmacodynamic effect that appears to be unrelated to any pharmacokinetics interaction. These observations, however, need to be confirmed in the actual patient population (Table 6.1).
Table 6.1
Effects of co-administered antimalarial drugs on the pharmacokinetics of antimalarials
Population | Design | N | Effect drug dosing | Affect drug dosing | Effects of antimalarials on antimalarial /metabolite PK | Reference | ||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
t | Analyte | AUC | Cmax | Cmin | Tmax | Vd/F | CL/F | t1/2 | ||||||
Amodiaquine | Healthy (Nigeria, all M) Age: 22–35 years Wt. 53–72 kg | Open label Prospective Cross over | 10 | 500 mg × 1 orally | 600 mg × 1 orally 24 h before halofantrine | Halofantrine | ↔ | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Omoruyi et al. (2007) |
Amodiaquine | Healthy (African, 10 M) Age: 24.4 years (mean) Wt: 67.3 kg (mean) | Randomized Prospective Cross over | 13 | 4 mg/kg × 1 orally | 10 mg/kg × 1 orally | Artesunate | ↔ | ↔ | ND | ↔ | ND | ND | ND | Orrell et al. (2008) |
Amodiaquine | Healthy (African, 10 M) Age: 24.4 years (mean) Wt: 67.3 kg (mean) | Randomized Prospective Cross over | 13 | 4 mg/kg × 1 orally | 10 mg/kg × 1 orally | Dihydroartemisinin | ↓ (67 %) | ↓(51 %) | ND | ↔ | ↑(192 %) | ↔ | ↑(157 %) | Orrell et al. (2008) |
Artemether | Healthy male Thai volunteers Age: 20–29 years old Wt: 49–57 kg | Prospective Open label Cross over | 8 | 750 mg orally × 1 | 300 mg orally × 1 | Mefloquine | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Na-Bangchang et al. (2000) |
Artemether | Healthy male Thai volunteers Age: 20–29 years old Wt: 49–57 kg | Prospective Open label Cross over | 8 | 600 mg orally × 1 | 300 mg orally × 1 | Quinine | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Na-Bangchang et al. (2000) |
Artemether | Healthy male Thai volunteers Age: 20–29 years old Wt: 49–57 kg | Prospective Open label Cross over | 8 | 45 mg orally × 1 | 300 mg orally × 1 | Primaquine | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Na-Bangchang et al. (2000) |
Artemether-lumefantrine | Healthy male volunteers Age: 19–50 years old Wt: 54.5–90.6 kg | Prospective Randomized Double blind Parallel group | 14 | 10 mg/kg iv over 2 h × 1 | 80 mg/480 mg (artemether/lumefantrine) orally × 6 doses over 60 h | Quinine | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Lefevre et al. (2002) |
Artemether | Thai patients with uncomplicated falciparum malaria | Open label Prospective Parallel group | 10 vs. 17 (control) | 750 mg orally × 1 (24 h post artemether) | 300 mg orally × 1 | Mefloquine | ↓(27 %) | ↓(29 %) | ND | ↑(133 %) | ND | ND | ↔ | Na-Bangchang et al. (1995) |
Artemether and lumefantrine | Healthy volunteers Age: 33.7 years (mean) Wt: 73.6 kg | Open label Prospective Randomized Parallel group | 14 | 1,000 mg orally divided in 3 doses over 12 h | 80 mg artemether/480 mg lumefantrine orally every 12 h × 6 doses | Mefloquine | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Lefevre et al (2000) |
Artemether | Healthy Thai volunteers (all M) Age: 21–28 years Wt: 45–70 kg | Open label Prospective Randomized Cross over | 8 | 100 mg orally × 1 | 300 mg orally × 1 | Pyrimethamine | ↔ | ↑(44 %) | ND | ↔ | ↓(15 %) | ↔ | ↔ | Tan-ariya et al. (1998) |
Artemisinin | Healthy Vietnamese males Age: 21–45 years old Wt: 44–73 kg | Open label Prospective Randomized | 10 | 100 mg orally × 1 | 500 mg orally × 1 | Artesunate (dihydroartemisinin) | ↑(193 %) | ↑(69 %) | ND | ND | ND | ↓(66 %) | ↑(196 %) | Zhang et al. (2001) |
Artesunate | Healthy (African, 10 M) Age: 24.4 years (mean) Wt: 67.3 kg (mean) | Randomized Prospective Cross over | 13 | 4 mg/kg × 1 orally | 10 mg/kg × 1 orally | Amodiaquine | ↔ | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Orrell et al. (2008) |
Artesunate | Healthy (African, 10 M) Age: 24.4 years (mean) Wt: 67.3 kg (mean) | Randomized Prospective Cross over | 13 | 4 mg/kg × 1 orally | 10 mg/kg × 1 orally | Amodiaquine (desethylamodiaquine) | ↓(65 %) | ↔ | ND | ↓(60 %) | ↔ | ↑(164 %) | ↔ | Orrell et al. (2008) |
Artesunate | Healthy (Karen, 8 M) Age: 33 years (median) Wt: 53 kg (median) | Open label Prospective Randomized Cross over | 12 | 1,000 mg atovaquone + 400 mg proguanil orally × 3 doses | 250 mg orally × 3 doses | Atovaquone | ↔ | ↔ | ↔ | ↔ | ↔ | ↔ | ↔ | van Vugt et al. (1999) |
Artesunate | Healthy (Karen, 8 M) Age: 33 years (median) Wt: 53 kg (median) | Open label Prospective Randomized Cross over | 12 | 1,000 mg atovaquone + 400 mg proguanil orally × 3 doses | 250 mg orally × 3 doses | Proguanil | ↔ | ↔ | ↔ | ↔ | ↔ | ↔ | ↔ | van Vugt et al. (1999) |
Artesunate | Healthy (Karen, 8 M) Age: 33 years (median) Wt: 53 kg (median) | Open label Prospective Randomized Cross over | 12 | 1,000 mg atovaquone + 400 mg proguanil orally × 3 doses | 250 mg orally × 3 doses | Proguanil (cycloquanil) | ↔ | ↔ | ↔ | ↔ | ↔ | ↔ | ↔ | van Vugt et al. (1999) |
Artesunate | Thai subjects with acute, uncomplicated falciparum malaria | Open label Prospective Randomized Parallel group | 8 (vs. 12 in control group) | 750 mg orally × 1 then 500 mg orally 6 h later | 200 mg orally × 1 | Mefloquine | ↔ | ↔ | ND | ↔ | ↑(27 %) | ↑(163 %) | ↔ | Karbwang et al. (1994) |
Artesunate | Healthy Vietnamese males Age: 21–45 years old Wt: 44–73 kg | Open label Prospective Randomized | 10 | 500 mg orally × 1 | 100 mg orally × 1 | Artemisinin | ↓(33 %) | ↓(25 %) | ND | ND | ↑(49 %) | ↔ | Zhang et al. (2001) | |
Atovaquone | Thai patients with acute falciparum malaria infection | Open label Prospective Parallel group | N = 4 (control) N = 12 (combination) | 200 mg orally twice daily for 3 days | 500 mg orally twice daily × 3 days | Proguanil | ↔ | ND | ND | ND | ND | ↔ | ↔ | Edstein et al. (1996) |
Atovaquone | Healthy (Caucasian, 9 M) Age: 26 years (median) Wt: 62.6 kg (median) | Open label Prospective Randomized Cross over | 18 | 400 mg orally daily × 3 days (steady-state) | 1,000 mg orally daily for 3 days | Proguanil | ↔ | ↓(7 %) | ND | ↔ | ↔ | ↔ | ↔ | Gillotin et al. (1999) |
Atovaquone | Healthy (Caucasian, 9 M) Age: 26 years (median) Wt: 62.6 kg (median) | Open label Prospective Randomized Cross over | 18 | 400 mg orally daily × 3 days (steady-state) | 1,000 mg orally daily for 3 days | Proguanil (cycloguanil) | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Gillotin 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 | Dapsone | ND (see text) | ND | ND | ND | ND | ND | ND | Adedoyin et al. (1998) |
Chloroquine | Healthy volunteers Age: 18–55 years Wt: > 60 kg | Prospective Randomized Double blind Parallel group | 20 | 900 mg orally daily × 2 days | 600 mg orally daily × 2 days, then 300 mg orally × 1 | Tafenoquine | ↔ | ↔ | ND | ND | ND | ND | ↔ | Miller et al. (2013) |
Chloroquine | Healthy volunteers | Open label Prospective Randomized Parallel groups | 8 | 1,500 mg/75 mg orally × 1 | 600 mg orally × 1 | Pyrimethamine | ↔ | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Obua et al. (2006) |
Chloroquine | Healthy volunteers | Open label Prospective Randomized Parallel groups | 8 | 1,500 mg/75 mg orally × 1 | 600 mg orally × 1 | Sulfadoxine | ↔ | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Obua et al. (2006) |
Dapsone | Healthy volunteers | Open label Prospective Cross over | 7 | 25 mg orally × 1 | 100 mg orally × 1 | Pyrimethamine | ND | ↔ | ND | ND | ↔ | ND | ↔ | Ahmad and Rogers (1980) |
Dihydroartemisinin | Healthy Thai male volunteers Age: 23–28 years old Wt: 51–57 kg | Open label Prospective Randomized Cross over | 10 | 750 mg orally × 1 | 300 mg orally × 1 | Mefloquine | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Na-Bangchang et al. (1999) |
Mefloquine | Healthy Thai volunteers Age: 21–38 years Wt: 53–65 kg | Open label Prospective Cross over | 9 | 45 mg orally × 1 | 10 mg/kg orally × 1 | Primaquine | ND | ↔ | ND | ↔ | ND | ND | ↔ | Edwards et al. (1993) |
Mefloquine | Healthy Thai volunteers Age: 21–38 years Wt: 53–65 kg | Open label Prospective Cross over | 9 | 45 mg orally × 1 | 10 mg/kg orally × 1 | Primaquine (carboxyprimaquine) | ↔ | ↔ | ND | ↔ | ND | ND | ND | Edwards et al. (1993) |
Mefloquine | Healthy male Thai volunteers Age: 20–29 years old Wt: 49–57 kg | Prospective Open label Cross over | 8 | 300 mg orally × 1 | 750 mg orally × 1 | Artemether | ↔ | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Na-Bangchang et al. (2000) |
Mefloquine | Healthy male Thai volunteers Age: 20–29 years old Wt: 49–57 kg | Prospective Open label Cross over | 8 | 300 mg orally × 1 | 750 mg orally × 1 | Artemether (dihydroartemisinin) | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Na-Bangchang et al. (2000) |
Mefloquine | Healthy male Thai volunteers Age: 24–47 years Wt: 50–65 kg | Open label Prospective Randomized Cross over | 7 | 600 mg orally × 1 | 750 mg orally × 1 | Quinine | ↔ | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Na-Bangchang et al. (1999) |
Mefloquine | Patients with symptomatic plasmodium falciparum malaria | Open label Prospective Randomized Parallel group | 18 vs. 20 (control) | 500 mg orally × 2, then 250 mg twice daily for 4 days (control)—total 3 g 500 mg orally, 750 mg orally, then 250 mg 3 times daily for 1 day—total 2 g (treatment group) | 250 mg orally 3 times daily × 1 day | Artemisinin | Note different dose between control vs. treatment ↑(38 %) | ↔ | ND | ↔ | ↓(38 %) | ↓(38 %) | ↔ | Alin et al. (1996) |
Mefloquine | Healthy subjects Age: 33.7 years (mean) Wt: 73.6 kg | Open label Prospective Randomized Parallel group | 14 | 80 mg artemether/480 mg lumefantrine orally ever 12 h × 6 doses | 1,000 mg orally divided in 3 doses over 12 h | Artemether (after single dose) | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Lefevre et al. (2000) |
Mefloquine | Healthy subjects Age: 33.7 years (mean) Wt: 73.6 kg | Open label Prospective Randomized Parallel group | 14 | 80 mg artemether/480 mg lumefantrine orally every 12 h × 6 doses | 1,000 mg orally divided in 3 doses over 12 h | Artemether (after multiple doses) | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Lefevre et al. (2000) |
Mefloquine | Healthy subjects Age: 33.7 years (mean) Wt: 73.6 kg | Open label Prospective Randomized Parallel group | 14 | 80 mg artemether/480 mg lumefantrine orally every 12 h × 6 doses | 1,000 mg orally divided in 3 doses over 12 h | Dihydroartemisinin (after single dose) | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Lefevre et al. (2000) |
Mefloquine | Healthy subjects Age: 33.7 years (mean) Wt: 73.6 kg | Open label Prospective Randomized Parallel group | 14 | 80 mg artemether/480 mg lumefantrine orally every 12 h × 6 doses | 1,000 mg orally divided in 3 doses over 12 h | Dihydroartemisinin (after multiple doses) | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Lefevre et al. (2000) |
Mefloquine | Healthy subjects Age: 33.7 years (mean) Wt: 73.6 kg | Open label Prospective Randomized Parallel group | 14 | 80 mg artemether/480 mg lumefantrine orally every 12 h × 6 doses | 1,000 mg orally divided in 3 doses over 12 h | Lumefantrine | ↓(44 %) | ↓(29 %) | ND | ↔ | ND | ND | ↔ | Lefevre et al. (2000) |
Mefloquine | Healthy Thai male volunteers Age: 23–28 years old Wt: 51–57 kg | Open label Prospective Randomized Cross over | 10 | 300 mg orally × 1 | 750 mg orally × 1 | Dihydroartemisinin | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Na-Bangchang et al. (1999) |
Mefloquine | Healthy male volunteers Age: 28.9 (mean) Wt: 77 kg | Open label Prospective Cross over | 20 | 200 mg orally daily × 3 | 250 mg orally daily × 3 | Artesunate (day 1) | ND | ↔ | ND | ↔ | ND | ND | ND | Davis et al. (2007) |
Mefloquine | Healthy male volunteers Age: 28.9 (mean) Wt: 77 kg | Open label Prospective Cross over | 20 | 200 mg orally daily × 3 | 250 mg orally daily × 3 | Dihydroartemisnin (day 1) | ↔ | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Davis et al. (2007) |
Mefloquine | Healthy male volunteers Age: 28.9 (mean) Wt: 77 kg | Open label Prospective Cross over | 20 | 200 mg orally daily × 3 | 250 mg orally daily × 3 | Artesunate (day 3) | ND | ↔ | ND | ↔ | ND | ND | ND | Davis et al. (2007) |
Mefloquine
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