Malaria and HIV infection are 2 of the most pernicious infectious diseases in the developing world. Malaria is caused by Plasmodium parasites and transmitted by the female Anopheles mosquito.1 The World Health Organization (WHO) estimated that in 2010, 216 million episodes of malaria led to 655,000 deaths worldwide, with 86% of these deaths in children younger than 5 years.2 HIV infects over 30 million persons world wide, with the bulk of HIV and malaria co-infection residing in sub-Saharan Africa.3 HIV co-infection rates have been reported to be 11% in children with malaria undergoing hospital admission in certain regions of sub-Saharan Africa.4 HIV infection increases the frequency and severity of malaria. In children, HIV infection leads to an increased risk of severe malaria and malarial treatment failure compared with HIV-uninfected children.5 Although the availability of antiretroviral therapy (ART) has expanded in Africa, multiple complicating factors must be considered in the context of malaria co-infection, including the potential for clinically important drug–drug interactions between ART and antimalarial therapy.
Artemisinin-based combination therapy (ACT) is recommended by WHO as first line for uncomplicated falciparum malaria. Artemisinin, originating in China from the plant qinghao (Artemisia annua L. or sweet wormwood), is a potent antimalarial responsible for rapid decline of parasite burden and resolution of clinical symptoms.6 Due to the short elimination half-life (typical 1–3 hours) of artemisinins,7,8 recommendations for the treatment of uncomplicated malaria advocate use of artemisinins in combination with long-acting partner drugs, including lumefantrine (LR) which has an elimination half-life of 3–6 days,9 to ensure elimination of residual parasites and to diminish selection for artemisinin resistance. Artemether–lumefantrine (AL) is one of the most widely used ACTs in the world and adopted in 48 countries as first-line therapy for uncomplicated falciparum malaria, including patients with HIV co-infection.10 True treatment failure (recrudescence) is uncommon with multiple studies showing the drug is effective.11–13 However, for patients within whom pharmacokinetic (PK) exposure to AL may be reduced (eg, in the context of enzyme inducers or pregnancy), recrudescence rates may increase and in the context of pregnancy have been reported to be higher.14
ACT pharmacology is complex, and significant drug–drug interactions with ART, which may impact on outcomes, are expected. Artemether (ARM) is metabolized by the cytochrome P450 (CYP) enzymes including CYP2B6 and CYP3A4 to active dihydroartemisinin (DHA), which is further metabolized (via glucuronidation and/or oxidation) to inactive products.9,15,16 Metabolism of LR is also mediated by CYP3A4.17 Efavirenz (EFV), one of commonly prescribed ART, is increasingly used for HIV in sub-Sahara Africa in setting endemic for malaria. EFV induces CYP 3A4 and 2B6 activity.18,19 To assess interactions between AL and EFV, we performed a standard drug–drug PK interaction evaluation in healthy adult volunteers.
General Study Design
This was an open-label 2-period crossover study in healthy adults (Fig. 1). Subjects were recruited based on the following inclusion criteria: (1) age 21–60 years; (2) within 20% (±) of ideal body weight; (3) weight at least 50 kg; and (4) screening laboratory tests that were normal or deemed not clinically significant by the study physician. Female subjects required a negative pregnancy test and agreed to 2 forms of birth control. Exclusion criteria included the following: (1) use of illicit drugs or alcohol; (2) use of drugs known to inhibit or induce CYP enzymes or known to be substrates of CYP enzymes; (3) pregnancy or breast-feeding; (4) history of acute or chronic illness, including diabetes, hypertension, coronary artery disease, psychiatric illness, renal or hepatic impairment, hypokalemia, hypomagnesemia, or hypercholesteremia; and (5) family history of corrected QT prolongation or conditions known to prolong the corrected QT interval, such as cardiac arrhythmias, bradycardia, or severe heart disease.
The study was approved by the University of California, San Francisco Committee on Human Research, and conducted at the Clinical Research Center, San Francisco General Hospital. All subjects read and signed the informed consent before participation. Enrolled subjects received 6 doses of co-formulated AL (Coartem, Novartis), 80/480 mg-twice daily (study days: 1–4). Dose 1 was given on day 1 in the evening to permit the sixth dose to be given in the morning on day 4 and permit intensive PK sampling during the day. PK sampling on days 4–7 was for ARM/DHA and day 4–15 for LR. This regimen was followed by a washout period of at least 2 weeks (following study day 15), which in turn was followed by a 26-day course of EFV 600 mg once daily (study days: 16–41) The washout period did not count toward the sequence of study days, (thus EFV started on study day 16). EFV was initially administered alone (study days: 16–27) and then given concomitantly with a second 6-dose course of AL 80/480-mg twice daily (study days: 28–31). Subjects were instructed to take all AL doses with food to optimize absorption and asked to record the time of dose and food intake in a diary. Subjects were not allowed to take alcohol and any medications known to modulate CYP enzymes during the study period. Study personnel contacted subjects by phone or e-mail before each visit to evaluate medication/dietary compliance and address questions. Study participants were admitted into the Clinical Research Center the night before all intensive PK collections, and were discharged after a 24-hour blood collection.
Subject Safety Monitoring
A physical examination, complete blood count with differential, comprehensive metabolic chemistry panel (CMP including serum electrolytes, glucose, blood urea nitrogen, creatinine, and liver function tests), fasting lipid panel, and electrocardiogram (ECG) were performed before enrollment and on the last day of the study. A serum HIV antibody test and urine tests for drugs of abuse were carried out at the screening visit. Female subjects had a pregnancy test within 48 hours before receiving study drugs. Additional laboratory and safety tests (complete blood count, CMP, lipid panel and ECG) were done after completion of each 3-day course of AL and at the day 10 of EFV administration. Standard audiometry tests were conducted at baseline, during the washout and after completion of the second course of AL. All subjects returned for repeat laboratory tests 2 and 4 weeks after study completion.
Compliance was monitored through review of patient diaries and pill counts, and subjects were asked to recount any untoward effects during study participation. All adverse events were classified according to the Division of AIDS Table for Grading the Severity of Adult Adverse Experiences.20 Follow-up of serious adverse events was at the discretion of study physicians.
PK Sample Collection and Processing
Intensive serial PK sampling for ARM, DHA, and LR was conducted on study day 4 (AL alone) and 31 (with co-administration of EFV). Blood samples were collected before and then 0.5. 1, 2, 4, 6, 8, 12, 24, 48, and 72 hours after the sixth AL dose (study days 4 and 31) for determination of ARM, DHA, and LR plasma concentrations. Blood samples were collected at 96, 120, 168, 216, and 264 hours for analysis of LR only. Steady state PK sampling for analyses of plasma levels of EFV alone (study day 26) and during co-administration of AL (study day 31) was conducted before and after 1, 2, 4, 6, 8, 12, and 24 hours after EFV administration (Fig. 1).
Blood samples (6 mL) were drawn into heparin and EDTA-containing tubes for subsequent analyses of ARM/DHA/LR and EFV, respectively. ARM/DHA/LR tubes were immediately placed on ice and centrifuged at 800g for 10 minutes at 4°C. The resulting plasma was split into aliquots and kept at −70°C until analysis.
Plasma Samples Analysis
ARM and DHA were analyzed from 500 μL plasma samples using a liquid chromatography tandem mass spectrometry method, as previously described.21 The lower limit of quantification (LLOQ) was 2.0 ng/mL, and the calibration range was 2.0–200 ng/mL. During sample analysis, the coefficient of variation (CV%) for quality control samples ranged from 6.4 to 10.1 for DHA and 6.9 to 10.2 for ARM. LR concentration was determined from 200 μL plasma samples using a high-performance liquid chromatography–ultraviolet detection (HPLC-UV) method with a linear calibration range of 50–10,000 ng/mL, as previously described.22 The CV% range during analysis was 5.6%–11.7%. EFV concentrations were determined with an HPLC-UV method using reserpine as the internal standard. Briefly, a 200 μL plasma sample was mixed with 100 μL reserpine (0.5 μg/mL in 25% acetonitrile) followed by vortex mixing with 700 μL acetonitrile to precipitate proteins, then 700 μL of the supernatant was dried and reconstituted with 200 μL mobile phase solvent, and 40 μL was injected onto a Waters Symmetry shield C8 column (3.9 × 150 mm, 5 μm) and eluted with a mixture (55:45) of 25 mM sodium phosphate (pH 6.9) and acetonitrile in isocratic mode at a flow rate of 0.7 mL/min. The detector was a photodiode-array detector set at λ = 247 nm. The LLOQ was 100 ng/mL. The CV during the analysis was less than 8% at all quality control levels.
PK and Statistical Data Analysis
All PK parameters for ARM, DHA, and LR were estimated using non-compartmental analysis via the linear up-log down trapezoidal rule in conjunction with first-order input using WinNonlin 5.2.1 (Pharsight Corporation, Mountain View, CA). Samples below the LLOQ were treated as missing data except for the predose drug concentration, which was set at 0 if below LLOQ. For the antimalarial compounds, the area under the plasma concentration versus time curve (AUC) was calculated as AUC from 0 to the last sampling or measurable time point (AUC0-last) and from 0 to time infinity (AUC0–∞). For EFV, the AUC was estimated under steady state conditions and thus the AUC from 0 time to the end of the dosing interval was estimated (AUC0–24 hrs). For ARM, DHA, and LR, the extrapolated area to ∞ for AUC0-∞ was determined by dividing the last measured concentration by the terminal elimination rate constant (lambda z or k). Extrapolation to infinity was only carried out if there were at least 3 measurable concentrations following the peak concentration. Lambda z (k) was estimated using the program's “best fit” feature combined with fine tuning manually in some cases. Sample size was selected to test the hypothesis that EFV co-administration would reduce LR exposure (AUC) by 40% with an 80% power and 5% significance level. All reported PK parameters except for tmax were compared between groups using Wilcoxon signed-rank test calculated with R-2.14.1 for 2 group comparisons. For the purpose of paired analysis, specific PK parameters for ARM and DHA were only reported if sufficient data for both PK study periods (days 4 and 31) were available.
Demographics and Safety
Seventeen subjects were enrolled, and 12 completed the study. Reasons for withdrawal were (1) central nervous system disturbances with EFV dosing (n = 1), (2) incorrect study drug dosing and withdrawal by the study physician (n = 1), (3) rash after AL administration (n = 1), and (4) elective study discontinuation for personal reasons (n = 2). The 12 participants included 10 males and 2 females with a mean age of 36 years (range: 24–53 years) and mean height, weight, and body mass index of 176 cm (165–192 cm), 79.5 kg (64.7–92.5 cm), and 26 (21–30 kg/m2), respectively.
Adverse events reported during the study were mild and transient. One subject developed a rash 3 days after AL initiation (leading to withdrawal), a second subject experienced central nervous system disturbances, and a third subject experienced a mild change in audiology results at study completion compared with baseline; a change deemed of borderline clinical significance. Laboratory tests and ECG results were all within normal limits.
The Impact of EFV on ARM and DHA Disposition
PK results for ARM, DHA, and LR are summarized in Table 1. A trend toward a decrease in most exposure estimates during co-administration was evident. Most notably, a nonsignificant trend toward a lower AUClast [−51% (P = 0.084)] was observed, with t1/2 decreasing by 44% (P < 0.05). The estimated reduction was not statistically significant but was large enough to possibly be considered clinically important. Due to more rapid conversion of ARM to DHA during co-administration with EFV, more data points fell below LLOQ (2 ng/mL). AUClast could not be estimated in 2 subjects due to insufficient concentration data points above LLOQ. Moreover, because estimation of AUC0–∞ requires at least 3 data points defining the terminal elimination phase of the curve, sufficient data for AUC0-∞ was only available in 7 of the 12 subjects during coadministration with EFV. Paired analysis for ARM parameters was possible in 10 of 12 subjects for AUClast and 7 of 12 subjects for AUC0–∞.
In contrast to results for ARM, EFV had a significant impact on DHA exposure as measured by changes in Cmax, AUClast, AUC0-∞, and t1/2 which decreased, compared with exposure without co-administration, by 38% (P = 0.021), 46% (P = 0.005), 39% (P = 0.010) and from 1.89 to 1.65 hours (P = 0.032), respectively. The DHA to ARM AUC ratio (representing conversion kinetics for ARM to DHA) was not significantly altered by co-administration (median AUClast ratio is 3.47 for AL alone versus 3.88 for AL + EFV, P = 0.684). Mean (±SD) plasma concentration–time profiles of ARM and DHA are represented in Figure 2.
Effects of EFV on LR Disposition
Day-7 LR levels are commonly used to predict therapeutic outcome and are represented by the LR values collected 120 hours after the last dose. Upon co-administration of AL with EFV, LR exposure at 120 hours (day 7) decreased 46% from 1020 ± 478 (AL alone) to 554 ± 432 ng/mL (AL+EFV), (P = 0.002). Other PK parameters were not altered significantly (Cmax, t1/2, AUClast, and AUC0–∞) (P > 0.05). Specifically, AUClast and AUC0–∞ were decreased by 21% (P = 0.102) and 22% (P = 0.067), respectively (Table 1). One subject was excluded from paired analysis of LR PK parameters, as samples were available only up to 24 hours during the second study period. Two subjects were excluded from paired analysis of day-7 LR levels as the concentration was not available at the time point in 1 period. The mean (±SD) plasma concentration–time profile of LR is shown in Figure 2.
Effects of AL on EFV Disposition
For EFV, PK parameters (Cmax, t1/2, and AUC0–24) did not change to clinically significant levels with AL coadministration. Specifically, the AUC0–24 decreased by 17% (P = 0.034) (Table 2), suggesting no important effect on EFV PK exposure. The mean (±SD) plasma concentration–time profile of EFV is shown in Figure 3.
The WHO recommends ACT for the treatment of uncomplicated falciparum malaria. Although resistance has been suggested due to reports of prolonged parasite clearance,23 ACTs consistently provide excellent efficacy for the treatment of uncomplicated malaria.11–13,24,25 However, ACT efficacy has not been systematically studied in the context of co-administration of drugs subject to clinically relevant drug-drug interactions and the impacts of such drugs on the ACT PKs has been little studied. This is the first study evaluating the effect of the widely prescribed antiretroviral drug EFV on the disposition of AL in HIV-seronegative healthy adults where the conditions for this intensive PK study were carefully controlled. The most concerning finding was a 50% reduction in the AUC of DHA, the active metabolite of ARM, during exposure to EFV and the significant decrease in day-7 levels for LR. Most recently, a separate study carried out in HIV-infected patients in Uganda has reported similar findings.26 Significant decreases in exposure to artemisinins may be particularly relevant given that ACT treatment for uncomplicated malaria is for only 3 days. Both ARM and DHA have potent antimalarial effects and contribute to rapid clearance of parasites. Diminished concentrations due to drug–drug interactions may alter the time course or extent of parasite elimination.
We found that when AL was given with EFV, all exposure parameters for DHA decreased significantly, compared with administration alone, results consistent with the study in Uganda.26 Results for ARM did not achieve statistical significance, however, a trend toward diminished exposure during co-administration with EFV was evident: Pseudomedian percent reduction of AUClast (n = 10) with 90% confidence interval for ARM is −43%(−66, −0.05), P = 0.084; in comparison, the study in Uganda reported a 79% reduction (n = 22) with a median ratio of 0.1 (0.03, 2.3), P < 0.01, a higher magnitude but wider range. Two of 12 subjects in our study versus 8 of 30 in their study were excluded from analysis of AUClast for ARM due to ARM concentration below LLOQ, results at least partially attributable to the induction of metabolism.
For LR, the most notable finding was the significant 46% decrease in day-7 concentrations with EFV co-administration, which is in contrast to the marginal effect on LR AUC (−22%, P = 0.067). AUC is the preferred parameter for assessing overall PK exposure. For field studies, measurement of day-7 levels offers a practical estimate of exposure. Due to the widespread use of day-7 monitoring in clinical trials, we reported findings for both day 7 and AUC.
EFV is a known inducer of CYP metabolism, especially of CYP3A4 and 2B6,18,19,27,28 suggesting ARM and LR exposure should decrease during co-administration. In contrast, DHA is primarily glucuronidated16 and EFV is not known to induce glucuronidation. Thus, the decrease in DHA exposure observed in this study is difficult to explain. One possibility would be a change in conversion of ARM to DHA. Because the ratio of DHA and ARM AUCs was unaltered, it is possible that absorption of ARM may have been altered due to gut CYP3A4 induction resulting in a decrease in plasma ARM level and thus a decrease in DHA level. Interestingly, our results for DHA are consistent with other reports showing EFV co-administration results in significant reduction in exposure to other UGT substrates, including pravastatin and the active deacetyl metabolite of norgestimate.28,29
Interactions between AL and other drugs have been reported. The CYP 3A4 inhibitor ketoconazole increases exposure to ARM, DHA, and LR by up to 2-fold.30 From our study with lopinavir/ritonavir (LPV/r),31 LR exposure was increased by 2-fold to 3-fold in healthy adults. Moreover, our fieldwork has revealed a lower re-infection rate when AL is co-administrated with LPV/r due to the extended elimination of LR.32 Grapefruit juice, which inhibits gut CYP3A4, increased exposure of ARM by 2-fold to 3-fold.33 Interaction with other enzyme inducers has been investigated. For nevirapine (NVP), clinical studies have yielded conflicting results with one report showing that NVP caused no significant change in LR AUC in non–malaria-infected subjects.26 In addition, 1 South African study reported a paradoxical increase in LR exposure with NVP.34
Although definitive studies on the relationship between artemisinin PK exposure and parasite clearance kinetics are lacking, an association between exposure and parasite clearance has been best described by White et al,9 whereby higher ARM and DHA AUC significantly decreased parasite clearance time, whereas LR AUC was less predictive. Current guidelines from the WHO for treatment of uncomplicated malaria emphasize the need for 3 days of adequate ACT exposure to ensure elimination of parasites.35 For LR, the change in day-7 levels may be of interest given that day-7 levels are increasingly considered predictive of clinical outcomes in terms of recrudescence (rare) or malaria re-infection rates. Of note, only 1 subject exhibited an LR day-7 level below 175 ng/mL, a threshold previously associated with the risk for treatment failure.36
The results from this study may be particularly relevant for children and pregnant women, who suffer the greatest burden from malaria infection, and for whom AL dosing may already be suboptimal. Of the 216 million malaria cases reported annually, 90% occur in sub-Saharan African, with the vast majority of cases affecting young children. In turn, up to 25% of pregnant women exhibit evidence of placental malaria and/or peripheral parasitemia.37–40 Both groups exhibit atypical PKs due to metabolic maturation in children or induction in pregnant women, resulting in lower than ideal concentrations of ACT components.41,42 Dosing for these populations has been largely extrapolated from nonpregnant adult data and adjusted for body weight, with guidelines ignoring developmental or physiological changes on drug disposition.43,44 This omission is underscored by prior experience with sulfadoxine–pyrimethamine, with children consistently prescribed lower than necessary doses, a practice that may have contributed to sulfadoxine–pyrimethamine resistance and “loss” of this previously effective regimen.45 For AL in particular, most evidence points to a lowering of exposure for LR in children41 and pregnant women46 with conflicting results for the artemisinins.47,48
Limitations of this study include that only 12 subjects were included, and this was done in malaria-uninfected participants as was done in the study by Byakika-Kibwika.26 This interaction needs to be confirmed in malaria-infected adults and children requiring use of AL for treatment.
In summary, we report a decrease in the PK exposure of active DHA and day-7 LR when AL is co-administered with EFV. Although only a nonsignificant trend toward diminished ARM exposure was observed, overall results for ARM and DHA suggest that further studies are warranted to decipher the clinical relevance of this interaction, especially when EFV and AL are to be co-administered to children and pregnant women.
The authors thank Kira Freeman as the study coordinator and Dr John Kornak at CTSI UCSF for his help with statistical analysis, and thank Dr Gilbert Lefevre at Novartis Pharmaceutical Co. for reviewing the article.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
efavirenz; artemether; dihydroartemisinin; lumefantrine; pharmacokinetic; drug–drug interaction