Pharmacokinetic interaction trial between co-artemether and mefloquine

Abstract

Forty-two healthy subjects were randomized in a parallel three-group design trial to investigate potential electrocardiographic and pharmacokinetic interactions between the new antimalarial co-artemether, a combination of artemether and lumefantrine (both of which are predominantly metabolized through CYP3A4), and mefloquine, another antimalarial described as a substrate (and possible inhibitor) of CYP3A4. Subjects were assigned to one of the three possible treatment groups (i.e., co-artemether alone or mefloquine alone or the combination of both). The dosage was 1000 mg mefloquine (divided into three doses over 12 h) followed 12 h later by six applications of co-artemether (40 mg artemether+480 mg lumefantrine each) over 60 h. The study medications were generally well tolerated after all treatments. Concomitant administration with mefloquine caused statistically significant lower (around 30–40%) plasma concentrations of lumefantrine than when co-artemether was administered alone. Even if important, this decrease in lumefantrine exposure was considered unlikely to impact clinical efficacy given the wide therapeutic index of co-artemether and the usual high variability in lumefantrine plasma levels, mostly and more importantly influenced by food intake. However, patients should be encouraged to eat at dosing times to compensate for this decreased bioavailability. The pharmacokinetics of artemether, DHA or mefloquine were not affected. Artemether concentrations significantly decreased over doses, independently of mefloquine co-administration, while DHA concentrations slightly (not significantly) increased. Therefore, no clinically relevant risks due to pharmacokinetic drug–drug interaction are expected at the enzymatic level following co-administration of co-artemether with CYP3A4 substrates with similar affinity to that of mefloquine.

Introduction

Malaria is a leading cause of morbidity and mortality in developing areas of the world, and remains a major health problem in endemic regions. It is estimated that 100 million clinical cases occur every year and that over two million people die every year from the disease (Wernsdorfer, 1994, Olliaro and Trigg, 1995). Prolonged and often inappropriate use of currently available drugs has led to the development of multiple drug-resistance in Plasmodium falciparum giving rise to a need for novel antimalarial drugs. In addition, many current antimalarial agents are associated with poor safety profiles and have complex dose regimens, creating a demand for new drugs which are well tolerated and simple to use.

Co-artemether (Fig. 1), is an oral, fixed-dose combination tablet of 20 mg artemether — a derivative of artemisinin — and 120 mg lumefantrine (previously known as benflumetol), a novel antimalarial synthesized and developed by the Academy of Military Medical Sciences (AMMS) in Beijing, People’s Republic of China. This combination was registered in China in 1992 for the treatment of falciparum malaria, and has been subsequently further developed by Novartis Pharmaceuticals (code research number CGP 56697). In Europe, it was first approved in January 1999 in Switzerland (trade name Riamet^®), including standby emergency treatment for travellers to regions where malaria is prevalent.

In China, drugs from the artemisinin group (like artemether) have been widely used and found to be effective for the treatment of malaria for many years. Artemether is characterized by a rapid onset of schizontocidal action, but has a short elimination half-life (2–3 h). Recrudescence is, however, frequent when artemether is employed as monotherapy (von Seidlein et al., 1997), unless high dosages are given over several days (Bunnag et al., 1991, Karbwang et al., 1994, White, 1996). Lumefantrine, by contrast, has a longer elimination half-life of up to 10 days (Thomsen et al., 1998, Lefèvre and Thomsen, 1999) and is associated with a low recrudescence rate (Ezzet et al., 1998, Skelton-Stroud and Mull, 1998), but has a slower onset of action. The rationale for the drug combination was to combine the benefits of the fast onset of action of artemether with the long duration of action and high cure rate of lumefantrine in a single oral formulation. Moreover, the short course of treatment with co-artemether (over 2 or 3 days) should lead to a much better compliance (Skelton-Stroud et al., 1998) which remains a major problem with long treatment regimens (Hien and White, 1993, Looareesuwan et al., 1996).

The therapeutic dosage regimen in adults consists of repeated administration of four doses of co-artemether given over 48 h, i.e., four consecutive doses of four tablets each (80 mg artemether+480 mg lumefantrine per dose) starting at the time of onset of symptoms or diagnosis, and then at 8, 24 and 48 h thereafter. In areas of multiple drug-resistant malaria, such as Thailand, and for stand-by emergency treatment, an intensive 3-day treatment course including two additional doses is recommended. This uses six consecutive doses of four tablets each (80 mg artemether+480 mg lumefantrine per dose) given at the time of onset of symptoms, after 8 h and twice daily thereafter for 2 days.

Clinical trials involving a total of over 2000 adult and pediatric patients with acute falciparum malaria have shown that co-artemether is very well tolerated and highly efficacious, even against multi-drug-resistant strains of the parasite (von Seidlein et al., 1997, Hatz et al., 1998, van Vugt et al., 1998, Skelton-Stroud et al., 1999, van Agtmael et al., 1999a).

The pharmacokinetics (PK) of artemether, its active metabolite dihydroartemisinin (DHA) and lumefantrine have been characterized after single oral doses of co-artemether in healthy volunteers and after multiple oral doses in paediatric and adult patients (aged 1–78 years) with falciparum malaria (Thomsen et al., 1998, Lefèvre and Thomsen, 1999, van Agtmael et al., 1999b). Decreases in artemether plasma concentrations (and rise in DHA levels) have been observed following multiple doses (Ezzet et al., 1998, Thomsen et al., 1998, Lefèvre and Thomsen, 1999). Other authors have also reported such findings in patients and healthy subjects receiving artemisinin (Ashton et al., 1996, Ashton et al., 1998). This has been ascribed to (auto)induction of artemisinin/artemether metabolizing enzyme(s). In vitro and in vivo data indicate that the cytochrome P450 3A4 (CYP3A4) iosenzyme predominantly contributes to the metabolism of artemether and lumefantrine (Lefèvre and Thomsen, 1999, van Agtmael et al., 1999c), while clinical data from a single dose study in a limited number of healthy subjects suggest no major contribution of CYP2D6 and CYP2C19 isoenzymes in the metabolism of artemether (van Agtmael et al., 1998).

Mefloquine (Fig. 1) is a widely used quinolinemethanol antimalarial which is described as being a substrate (and possibly an inhibitor) of CYP3A4 (Riviere and Back, 1986, Bangchang et al., 1992, Grace et al., 1998). Though it is generally well tolerated, mefloquine has the potential for inducing neuropsychiatric adverse events (e.g., dizziness, headache, sleep disturbances), some of which can be more serious (e.g., anxiety disorders, psychosis, convulsions), and cardiac side effects (e.g., circulatory disturbances, transient cardiac conduction alterations) (Karbwang et al., 1991, Laothavorn et al., 1992, Palmer et al., 1993, Fonteyne et al., 1996, Davis et al., 1996, Crevoisier et al., 1997). In particular, mefloquine was reported to enhance the QTc-prolonging effect of halofantrine (Nosten et al., 1993, Coyne et al., 1996), an antimalarial associated with QTc prolongation (Karbwang and Bangchang, 1994, Toivonen et al., 1994, Monlun et al., 1995), and with structural similarities to lumefantrine. Administration of co-artemether in the presence of mefloquine is probable in malaria patients, as co-artemether might be used following the failure of prophylaxis or treatment with mefloquine. Although co-artemether itself has not caused any QTc prolongation in healthy volunteers in a comparison study with halofantrine (Bindschedler et al., 1998), a possible clinically relevant drug–drug interaction with mefloquine was nevertheless investigated. Therefore, one objective of this study was to evaluate the potential cardiac effects of the study compounds, and in particular of the combined treatment (i.e., co-artemether+mefloquine). The other objective was to evaluate the effects on the pharmacokinetics of artemether, DHA, lumefantrine, and mefloquine of combined (sequential) administration of the two treatments (i.e., co-artemether and mefloquine) compared with the sole administration of each drug. In addition, a determination of whether co-artemether has an inductive effect on CYP3A4 activity was assessed by the urinary 6β-hydroxycortisol/cortisol ratio.

The present paper reports the pharmacokinetic findings while the results of the intensive ECG surveillance in relation to drug concentrations will be published separately (Bindschedler et al., submitted).