, 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 affecting the pharmacokinetics of various antimalarial drugs, including amodiaquine, artemether/lumefantrine, artemisinin derivatives, atovaquone, chloroquine, mefloquine, proguanil, and quinine.
4.1 Effects of Drugs on the Pharmacokinetics of Amodiaquine
Scarsi et al. (2014) studied the effects of steady-state nevirapine (200 mg)-based antiretroviral therapy containing zidovudine (300 mg) and lamivudine (150 mg) on the pharmacokinetics of amodiaquine and desethylamodiaquine in HIV-infected, but malaria-free, individuals using an open label, parallel control group design. Subjects received the combination of artesunate/amodiaquine (200/600 mg) orally daily for 3 days, but only the pharmacokinetics of amodiaquine and its major metabolite desethylamodiaquine were quantified. The major finding was that nevirapine-based antiretroviral therapy significantly reduced the exposures of both amodiaquine (204 vs. 145 ng h/mL, mean) and desethylamodiaquine (21,648 vs. 14,571 ng h/mL) compared to the nevirapine-naïve control group, respectively. No other pharmacokinetic differences were observed (i.e. maximum concentration (Cmax), time to reach maximum concentration (Tmax), area under the curve (AUC)metabolite/AUCamodiaquine ratio) for desethylamodiaquine but significant changes in Cmax (16.7 vs. 24.6 ng/mL, mean), Tmax (1 vs. 3 h), apparent oral clearance (CL/F) (4,165 vs. 2,775 L/h), apparent volume of distribution (Vd/F) (63,761 vs. 25,837 L) were observed for subjects receiving nevirapine compared to the controls, respectively. Nevirapine, being an inducer of Cytochrome P450 (CYP)3A4 and CYP2B6 (Lamson et al. 1999), could not have decreased the exposure of amodiaquine since it is known to be predominately metabolized by a single CYP2C8 pathway. Likewise, neither zidovudine nor lamivudine is known to affect CYPP450 metabolism, suggesting that other metabolic processes or pathways of amodiaquine or desethylamodiaquine, which remain to be determined, may have contributed to these findings. These data, however, should be interpreted in the context of some limitations of the study (i.e. small sample size, baseline differences between study groups, etc.), and it is not clear whether these findings can be generalized to the true patient population, because one must consider the interaction between malaria itself and the pharmacokinetics of these agents (Table 4.1).
Table 4.1
Effects of co-administered drugs on pharmacokinetics of antimalarials
Population | Design | N | Effect drug dosing | Affect drug dosing | Effects of drug on antimalarial/metabolite PK | Reference | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Analyte | AUC | Cmax | Cmin | Tmax | Vd/F | CL/F | t1/2 | |||||||
Nevirapine (+zidovudine/lamivudine) | HIV + but malaria free Age: 39.7 vs. 35.8 (control) years Wt: ND | Open label Prospective Parallel group | 10 (nevirapine) 11 (control) | Nevirapine (200 mg), zidovudine (300 mg), lamivudine (150 mg) orally twice daily × minimum 8 weeks (steady-state) | 200/600 mg (artesunate/amodiaquine) orally daily × 3 days | Amodiaquine | ↓(29 %) | ↔ | ND | ↓(67 %) | ↑(146 %) | ↑(50 %) | ↔ | Scarsi et al. (2014) |
Nevirapine (+zidovudine/lamivudine) | HIV + but malaria free Age: 39.7 vs. 35.8 (control) years Wt: ND | Open label Prospective Parallel group | 10 (nevirapine) 11 (control) | Nevirapine (200 mg), zidovudine (300 mg), lamivudine (150 mg) orally twice daily × minimum 8 weeks (steady-state) | 200/600 mg (artesunate/amodiaquine) orally daily × 3 days | Amodiaquine (desethylamodiaquine) | ↓(33 %) | ↔ | ND | ↔ | ND | ND | ND | Scarsi et al. (2014) |
Omeprazole | Healthy male volunteers of Dutch ethnicity Age: 19–26 years old Wt: 65–90 kg | Open label Prospective Cross over | 7 | 100 mg orally × 1 | 40 mg orally × 1 | Artemether | ↔ | ↔ | ND | ↔ | ↔ | ND | ↔ | van Agtmael et al. (1998) |
Omeprazole | Healthy male volunteers of Dutch ethnicity Age: 19–26 years old Wt: 65–90 kg | Open label Prospective Cross over | 7 | 100 mg orally × 1 | 40 mg orally × 1 | Artemether (dihydroartemisinin) | ↔ | ↔ | ND | ↔ | ↔ | ND | ↔ | van Agtmael et al. (1998) |
Rifampin | HIV-positive Ugandan undergoing TB treatment but without malaria | Open label Prospective Cross over (from rifampin-based TB treatment to no-rifampin TB treatment) | 5–6 | 80 mg/480 mg (artemether/lumefantrine) orally twice daily for 3 days | Steady-state dosing of rifampin (with other TB medications)—no dosing specified | Artemether-lumefantrine (artemether) | ↓(89 %) | ↓(83 %) | ND | ND | ND | ND | ↔ | Lamorde et al. (2013) |
Rifampin | HIV-positive Ugandan undergoing TB treatment but without malaria | Open label Prospective Cross over (from rifampin-based TB treatment to no-rifampin TB treatment) | 5–6 | 80 mg/480 mg (artemether/lumefantrine) orally twice daily for 3 days | Steady-state dosing of rifampin (with other TB medications)—no dosing specified | Artemether-lumefantrine (dihydroartemisinin) | ↓(85 %) | ↓(78 %) | ND | ND | ND | ND | ↔ | Lamorde et al. (2013) |
Rifampin | HIV-positive Ugandan undergoing TB treatment but without malaria | Open label Prospective Cross over (from rifampin-based TB treatment to no-rifampin TB treatment) | 5–6 | 80 mg/480 mg (artemether/lumefantrine) orally twice daily for 3 days | Steady-state dosing of rifampin (with other TB medications)—no dosing specified | Artemether-lumefantrine (lumetantrine) | ↓(68 %) | ND | ND | ND | ND | ND | ↔ | Lamorde et al. (2013) |
Ketoconazole | Healthy Caucasian subjects Age: 19–49 years old Wt: 61.4–87.4 kg | Open label Prospective Randomized Cross over | 16 | 80 mg/480 mg (artemether/lumefantrine) orally × 1 | 400 mg orally × 1, then 200 mg daily for 4 days | Artemether-lumefantrine (artemether) | ↑(140 %) | ↑(120 %) | ND | ↔ | ND | ND | ↑(32 %) | Lefevre et al. (2002) |
Ketoconazole | Healthy Caucasian subjects Age: 19–49 years old Wt: 61.4–87.4 kg | Open label Prospective Randomized Cross over | 16 | 80 mg/480 mg (artemether/lumefantrine) orally × 1 | 400 mg orally × 1, then 200 mg daily for 4 days | Artemether-lumefantrine (dihydroartemisinin) | ↑(70 %) | ↑(40 %) | ND | ↔ | ND | ND | ↔ | Lefevre et al. (2002) |
Ketoconazole | Healthy Caucasian subjects Age: 19–49 years old Wt: 61.4–87.4 kg | Open label Prospective Randomized Cross over | 16 | 80 mg/480 mg (artemether/lumefantrine) orally × 1 | 400 mg orally × 1, then 200 mg daily for 4 days | Artemether-lumefantrine (lumefantrine) | ↑(70 %) | ↔ | ND | ↔ | ND | ND | ↔ | Lefevre et al. (2002) |
Trimethoprim-sulfamethoxazole | HIV-infected (5 M) Age: 31 years (median) | Open label Prospective Cross over | 6 | 160/800 mg orally every 12 h × 1 week | 500 mg orally daily (with food) × 2 weeks | Atovaquone | ND (see text) | ND | ND | ND | ND | ND | ND | Falloon et al. (1999) |
Efavirenz | Healthy vs. HIV-infected on HIV-antiviral Age: 18–65 years | Open label Prospective | 18 (Healthy) 20 (HIV) | 250 mg atovaquone + 100 mg proguanil orally × 1 dose (prophylactic dose) | Steady-state 600 mg orally daily | Atovaquone | ↓(75 %) | ↓(44 %) | ND | ND | ND | ND | ND | van Luin et al. (2010) |
Lopinavir/Ritonavir | Healthy vs. HIV-infected on HIV-antiviral Age: 18–65 years | Open label Prospective | 18 (Healthy) 19 (HIV) | 250 mg atovaquone + 100 mg proguanil orally × 1 dose (prophylactic dose) | Steady-state 800/200 mg lopinavir/ritonavir orally daily | Atovaquone | ↓(74 %) | ↓(44 %) | ND | ND | ND | ND | ND | van Luin et al. (2010) |
Atazanavir/Ritonavir | Healthy vs. HIV-infected on HIV-antiviral Age: 18–65 years | Open label Prospective | 18 (Healthy) 19 (HIV) | 250 mg atovaquone + 100 mg proguanil orally × 1 dose (prophylactic dose) | 300/100 mg atazanavir/ritonavir orally daily | Atovaquone | ↓(44 %) | ↓(49 %) | ND | ND | ND | ND | ND | van Luin et al. (2010) |
Cimetidine | Healthy (all M) Age: 21–27 years old Wt: 63–68 kg | Open label Prospective Randomized Parallel control group | 5 | 600 mg orally × 1 | 400 mg orally daily × 4 days | Chloroquine | ND | ND | ND | ND | ↑(57 %) | ↓(53 %) | ↑(49 %) | Ette et al. (1987a) |
Cimetidine | Healthy (all M) Age: 21–27 years old Wt: 63–68 kg | Open label Prospective Randomized Parallel control group | 5 | 600 mg orally × 1 | 400 mg orally daily × 4 days | Chloroquine (monodesethyl-chloroquine) | ↓(47 %) | ↔ | ND | ↔ | ND | ND | ND | Ette et al. (1987a) |
Ranitidine | Healthy (all M) Age: 19–27 years old | Open label Prospective Randomized Parallel control group | 5 | 600 mg orally × 1 | 250 mg orally daily × 4 days | Chloroquine | ↔ | ND | ND | ND | ↔ | ↔ | ↔ | Ette et al. (1987b) |
Imipramine | Healthy volunteers Age: 23–28 years old Wt: 55–65 kg | Open label Prospective Randomized Cross over | 6 | 300 mg orally × 1 | 50 mg orally × 1 | Chloroquine | ND | ↔ | ND | ↔ | ↔ | ↔ | ↔ | Onyeji et al. (1993) |
Aspirin | Healthy volunteers (all M) | Open label Prospective Cross over | 8 | 600 mg orally × 1 | 325 mg orally × 1 | Chloroquine | ↔ | ↔ | ND | ND | ND | ND | ↔ | Raina et al. (1993) |
Acetaminophen | Healthy volunteers (all M) | Open label Prospective Cross over | 8 | 600 mg orally × 1 | 500 mg orally × 1 | Chloroquine | ↑(23 %) | ↑(17 %) | ND | ND | ND | ND | ↔ | Raina et al. (1993) |
Analgin | Healthy volunteers (all M) | Open label Prospective Cross over | 8 | 600 mg orally × 1 | 500 mg orally × 1 | Chloroquine | ↑(21 %) | ↑(25 %) | ND | ND | ND | ND | ↔ | Raina et al. (1993) |
Methylene blue | Healthy volunteers | Prospective Randomized Placebo-controlled Parallel group | 24 | 130 mg orally twice daily × 3 days | 40 mg/kg orally daily × 3 doses (1,000 mg × 1 day + 500 mg × 2 days for M patients; 750 mg × 1 day + 375 mg × 3 days for F patients) | Chloroquine | ↔ | ND | ND | ND | ND | ND | ↔ | Rengelshausen et al. (2004) |
Methylene blue | Healthy volunteers | Prospective Randomized Placebo-controlled Parallel group | 24 | 130 mg orally twice daily × 3 days | 40 mg/kg orally daily × 3 doses (1,000 mg × 1 day + 500 mg × 2 days for M patients; 750 mg × 1 day + 375 mg × 3 days for F patients) | Chloroquine (desethylchloroquine) | ↓(30 %) | ND | ND | ND | ND | ND | ↔ | Rengelshausen et al. (2004) |
Azithromycin | Healthy volunteers | Open label Prospective Parallel groups | 24 vs. 15 (control) | 1 g orally × 2 days, then 500 mg orally × 1 day | 1 g orally daily × 3 days | Chloroquine | ↔ | ↔ | ND | ND | ND | ND | ↔ | Cook et al. (2006) |
Azithromycin | Healthy volunteers | Open label Prospective Parallel groups | 24 vs. 15 (control | 1 g orally × 2 days, then 500 mg orally × 1 day | 1 g orally daily × 3 days | Chloroquine (desethylchloroquine) | ↔ | ↔ | ND | ND | ND | ND | ↔ | Cook et al. (2006) |
Promethazine | Healthy volunteers | Open label Prospective Parallel groups | 5 | 10 mg/kg orally daily on days 1 & 2, and 5 mg/kg orally × 1 on day 3 | 25 mg orally × 1, then 12.5 mg orally Q8H × 5 days | Chloroquine | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Gbotosho et al. (2008) |
Chlorpheiramine | Healthy volunteers | Open label Prospective Parallel groups | 5 | 10 mg/kg orally daily on days 1 & 2, and 5 mg/kg orally × 1 on day 3 | 8 mg orally × 1, then 4 mg orally Q8H × 7 days | Chloroquine | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Gbotosho et al. (2008) |
Promethazine | Healthy volunteers | Open label Prospective Parallel groups | 5 | 10 mg/kg orally daily on days 1 & 2, and 5 mg/kg orally × 1 on day 3 | 25 mg orally × 1, then 12.5 mg orally Q8H × 5 days | Chloroquine (in erythrocyte) | ↔ | ↔ | ND | ↔ | ND | ND | ↔ | Gbotosho et al. (2008) |
Chlorpheiramine | Healthy volunteers | Open label Prospective Parallel groups | 5 | 10 mg/kg orally daily on days 1 & 2, and 5 mg/kg orally × 1 on day 3 | 8 mg orally × 1, then 4 mg orally Q8H × 7 days | Chloroquine (in erythrocyte) | ↑(114 %) | ↑(24 %) | ND | ↔ | ND | ND | ↑(96 %) | Gbotosho et al. (2008) |
Metoclopramide | Healthy male volunteers Age: 24–44 years Wt: 47–60 kg | Open label Prospective Cross over | 7 | 750 mg orally × 1 | 10 mg orally × 1 | Mefloquine | ↔ | ↑(31 %) | ND | ND | ND | ND | ↔ | Na-Bangchang et al. (1991) |
Ampicillin | Healthy male Thai volunteers Age: 24–51 years Wt: 48–61 kg | Open label Prospective Cross over | 8 | 750 mg orally × 1 | 250 mg orally 4 times daily for 5 days | Mefloquine | ↔ | ↑(34 %) | ND | ↔ | ↓(27 %) | ↔ | ↓(14 %) | Karbwang et al. (1991) |
Tetracycline | Healthy mail Thai volunteers Age: 19–43 years Wt: 49–68 kg | Open label Prospective Randomized Parallel control | 11 (vs. 9 in control group) | 750 mg orally × 1 | 250 mg orally four times daily for 7 days | Mefloquine | ↔ | ↑(38 %) | ND | ↔ | ↓(33 %) | ↔ | ↓(25 %) | Karbwang et al. (1992) |
Cimetidine | Healthy male volunteers Age: 32.2 ± 2.6 years (mean ± SD) Wt: 64.8 ± 6.0 kg | Open label Prospective Cross over | 6 | 500 mg orally × 1 | 400 mg orally twice daily for 3 days | Mefloquine | ↑(38 %) | ↑(42 %) | ND | ↔ | ↔ | ↔ | ↔ | Kolawole et al. (2000) |
Cimetidine | Patients with ulcer Age: 34.8 ± 3.9 years (mean ± SD) Wt: 65 ± 2.1 kg | Open label Prospective Cross over | 6 | 500 mg orally × 1 | 400 mg orally twice daily for 3 days | Mefloquine | ↑(32 %) | ↑(21 %) | ND | ↔ | ↔ | ↔ | ↔ | Kolawole et al. (2000) |
Rifampin | Healthy Thai male volunteers Age: 24–35 years Wt: 57–72 kg | Open label Prospective Cross over | 7 | 500 mg orally × 1 | Steady-state 600 mg orally daily for 7 days then twice weekly for total of 56 days | Mefloquine | ↓(68 %) | ↓(19 %) | ND | ↔ | ND | ↑(281 %) | ↓(63 %) | Ridtitid et al. (2000) |
Rifampin | Healthy Thai male volunteers Age: 24–35 years Wt: 57–72 kg | Open label Prospective Cross over | 7 | 500 mg orally × 1 | Steady-state 600 mg orally daily for 7 days then twice weekly for total of 56 days | Mefloquine (carboxylic acid metabolite) | ↔ | ↑(47 %) | ND | ↓(76 %) | ND | ↔ | ↓(39 %) | Ridtitid et al. (2000) |
Ketoconazole | Healthy Thai male volunteers Age: 29.5 ± 8.4 years Wt: 61.5 ± 2.6 kg | Open label Prospective Randomized Cross over | 8 | 500 mg orally × 1 | 400 mg orally daily for 10 days | Mefloquine | ↑(79 %) | ↑(64 %) | ND | ↔ | ND | ND | ↑(39 %) | Ridtitid et al. (2005) |
Ketoconazole | Healthy Thai male volunteers Age: 29.5 ± 8.4 years Wt: 61.5 ± 2.6 kg | Open label Prospective Randomized Cross over | 8 | 500 mg orally × 1 | 400 mg orally daily for 10 days | Mefloquine (carboxylic acid metabolite) | ↓(28 %) | ↓(31 %) | ND | ↔ | ND | ND | ↔ | Ridtitid et al. (2005) |
Ritonavir | Healthy volunteers | Open label Prospective Cross over | 12 | 250 mg orally daily for 3 days, then once weekly for 4 weeks | 200 mg orally twice daily for 7 days, then same dose again for 7 days with last mefloquine dose | Mefloquine | ↔ | ↔ | ND | ND | ND | ↔ | ND | Khaliq et al. (2001) |
Ritonavir | Healthy volunteers | Open label Prospective Cross over | 12 | 250 mg orally daily for 3 days, then once weekly for 4 weeks | 200 mg orally twice daily for 7 days, then same dose again for 7 days with last mefloquine dose | Mefloquine (+) RS Mefloquine | ↔ | ↔ | ND | ND | ND | ↔ | ND | Khaliq et al. (2001) |
Ritonavir | Healthy volunteers | Open label Prospective Cross over | 12 | 250 mg orally daily for 3 days, then once weekly for 4 weeks | 200 mg orally twice daily for 7 days, then same dose again for 7 days with last mefloquine dose | Mefloquine (-) SR Mefloquine | ↔ | ↔ | ND | ND | ND | ↔ | ND | Khaliq et al. (2001) |
Ritonavir | Healthy volunteers | Open label Prospective Cross over | 12 | 250 mg orally daily for 3 days, then once weekly for 4 weeks | 200 mg orally twice daily for 7 days, then same dose again for 7 days with last mefloquine dose | Mefloquine (carboxylic acid metabolite) | ↔ | ↔ | ND | ND | ND | ND | ND | Khaliq et al. (2001) |
Efavirenz | Healthy vs. HIV-infected on HIV-antiviral Age: 18–65 years | Open label Prospective | 18 (Healthy) 20 (HIV) | 250 mg atovaquone + 100 mg proguanil orally × 1 dose (prophylactic dose) | Steady-state 600 mg orally daily | Proguanil | ↓(43 %) | ↔ | ND | ND | ND | ND | ND | van Luin et al. (2010)
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