Mefloquine pharmacokinetic-pharmacodynamic models: implications for dosing and resistance

Abstract

Antimalarial resistance develops and spreads when spontaneously occurring mutant malaria parasites are selected by concentrations of antimalarial drug which are sufficient to eradicate the more sensitive parasites but not those with the resistance mutation(s). Mefloquine, a slowly eliminated quinoline-methanol compound, is the most widely used drug for the treatment of multidrug-resistant falciparum malaria. It has been used at doses ranging between 15 and 25 mg of base/kg of body weight. Resistance to mefloquine has developed rapidly on the borders of Thailand, where the drug has been deployed since 1984. Mathematical modeling with population pharmacokinetic and in vivo and in vitro pharmacodynamic data from this region confirms that, early in the evolution of resistance, conventional assessments of the therapeutic response </=28 days after treatment underestimate considerably the level of resistance. Longer follow-up is required. The model indicates that initial deployment of a lower (15-mg/kg) dose of mefloquine provides a greater opportunity for the selection of resistant mutants and would be expected to lead more rapidly to resistance than de novo use of the higher (25-mg/kg) dose.

FIG. 1

Percent uptake of [³H]hypoxanthine compared to that in drug-free control wells for various mefloquine concentrations. The solid line shows the fit of the data and represents the predicted concentration-time profile for the population mean. The outer, dashed lines represent the 90% prediction intervals. The three panels show the fits for the following data sets: U.S. Armed Forces Research Institute of Medical Sciences (a), Wellcome Unit, Bangkok (b), and the Shoklo Malaria Research Unit (c).

FIG. 2

Simulated pharmacokinetic profiles for the two standard mefloquine doses, 15 and 25 mg/kg, obtained with the parameter estimates given in Table 1.

FIG. 3

Total malaria parasite burden versus time for the two standard mefloquine doses, 15 and 25 mg/kg, based on the PK/PD parameter estimate in Table 3. The initial parasite burden corresponds to a parasite count of approximately 100,000/μl, or 2% parasitemia, in an adult with falciparum malaria.

FIG. 4

Relationship between parasite clearance over time and maximum mefloquine concentration (C₀) in blood. In this example, P₀ is 10¹², a is 1.15/day, k is 0.036/day, k₁ is 3.45/day, γ is 2.5, and C₅₀ is 665.4 ng/ml.

FIG. 5

Relationship between parasite clearance over time and the slope of the concentration-effect curve (γ). In this example, P₀ is 10¹², a is 1.15/day, k is 0.036/day, C₀ is 1,200 ng/ml, k₁ is 3.45/day, and C₅₀ is 665.4 ng/ml.

FIG. 6

Relationship between parasite clearance over time and the MIC in vivo. In this example, P₀ is 10¹², a is 1.15/day, k is 0.036/day, C₀ is 1,200 ng/ml, k₁ is 3.45/day, and γ is 2.5.

FIG. 7

Relationship between parasite clearance over time and m (scalar value relating EC₉₀ in vitro to MIC in vivo). In this example, P₀ is 10¹², a is 1.15/day, k is 0.036/day, C₀ is 1,200 ng/ml, k₁ is 3.45/day, γ is 2.5, and EC₉₀ in vitro is 50.43 ng/ml.

FIG. 8

Relationship between parasite clearance over time and the ratio of maximum mefloquine C₀ to MIC (R). In this example, P₀ is 10¹², a is 1.15/day, k is 0.036/day, k₁ is 3.45/day, and γ is 2.5.

FIG. 9

Relationship between the minimum value of C₀ to MIC ratio (R_C) required to clear all parasites and the total body parasite burden on admission. In this example, a is 1.15/day, k is 0.036/day, k₁ is 3.45/day, and γ is 2.5.

FIG. 10

Time to recrudescence following treatment with mefloquine at 25 mg/kg as a function of MIC in vivo and killing rates (k₁). The z axis is the time to recrudescence, the y axis is the killing rate of mefloquine (k₁), and the x axis is the MIC in vivo. The pharmacokinetic parameters used in the simulation were the population mean values as described previously from studies in northwestern Thailand (11). Nonraised rectangles represent two possible scenarios: either the patient is cured or at day 7 the parasites are still detectable. This illustrates that for relatively drug-sensitive parasites (MIC, < 500 ng/ml) the infections are all cured with high killing rates and that with low killing rates recrudescences occur long after the conventional follow-up period of 28 days. Conversely, with highly resistant parasites, long follow-up (i.e., >42 days) is not necessary.