Human pharmacokinetics of halofantrine hydrochloride

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Humanpharmacokinetics of halofantrine

Human Pharmacokinetics of Halofantrine Hydrochloride Colin Broom Summary

Preliminary data on the pharmacokinetics of halojantrine and its N-desbutyl metabolite have been obtained almost exclusively from the healthy volunteer population. The assay method used in most studies has been high performance liquid chromatography (h.p.l.c.) with fluorescence detection in plasma, serum or whole blood, which has a sensitivity of 0.02 fl-molll (0.01 fl-glml) for halofantrine and 0.016 iunol/l (0.007 IJ,glml) for the N-desbutyl metabolite. The data indicate that the extent of absorption of halofantrine hydrochloride is low and variable, with no clearevidence ofincreased absorption above the 500-750 mg single doserange. The time to peak plasma concentration of halofantrine is approximately 6 h and the apparent terminal half-life is 1-2 days. There is evidence that the absorption of halofantrine may be markedly enhanced by the presence of high protein, high lipid contentfood and that its metabolismmay besaturable at highplasmaconcentrations. The valuefor tmaxfor the N -desbutylmetabolite followingsingle doses ofhalofantrine is about 12 h and its apparent terminal half-life is 3-5 days. Further studies are required to substantiate these pharmacokinetic data, ideally with a more sensitive assay in a larger population includingpatients. Introduction The technical problems associated with performing pharmacokinetic studies in malaria patients have meant that preliminary pharmacokinetic data have been almost exclusively derived from studies in healthy volunteers. However, the early clinical evaluation of halofantrine suggested that efficacy in the treatment of malaria could be increased by using a split dosing regimen of three 500 mg doses at 6 h intervals.

formulations have included a capsule and a suspension. Single doses studied to date range up to 2000 mg. The studies reviewed and the doses administered are presented in Table 1. Study 1 was a dose-rising study in which 14 healthy male subjects received a single dose of halofantrine. Six dose levels were studied with two or four subjects per dose level. Study 2 was a group comparative study in a total of 23 sub-

Methods Halofantrine hydrochloride has been mainly administered to man as tablets in pharmacokinetic studies. Alternative

Table I.

Director of Clinical Pharmacology, Smith Kline and French Research Ltd, The Frythe, Welwyn. Herts AL6 9AR. UK.

Pharmacokinetic studies

Healthy volunteers Dose levels Dose-rising study

750-2000 mg

Dose proportionality

250-1000 mg

Bioequivalence

SOOmg

Single vs multiple dose

500 mg or 500 mg X 3

16

Halofantrine in the treatment of multidrug-resistant malaria

jeers. Five or six subjects were studied at four dose levels. Study 3 compared the exposure to drug following administration of tablets, suspension and capsule in a three-way crossover study design in 12 subjects. In study 4 each of ten subjects was given a single dose of halofantrine followed at least 21 days later by three 500 mg doses at 6 h intervals. In the studies presented, subjects were studied in the fasting state and food of high protein, high lipid content was administered 4 hand 10 h after drug administration. Blood samples were taken at frequent intervals to at least 168 h after dosing. The assay methodology in most studies has been high performance liquid chromatography (h .p.l.c.) with fluorescence detection (Lin et al., 1985). Drug concentrations have been estimated in plasma, serum or whole blood and are therefore not strictly comparable between studies. The sensitivity of the assay in plasma is 0.02 umol/l (0.01 ug/ml) for halofantrine and 0.016 umol/l (0.007 ug/ml) for the N-desbutyl-halofantrine metabolite . A

radioimmunoassay was used in an early, rising-dose study , but there appeared [0 be cross-reaction between parent compound and metabolite. Due to instability of drug in biological fluids, samples for analysis needed to be stored at - 70°C. The following pharmacokinetic terms and methods have been used :

Ave, the area under the plasma concentration-time curve, which is an index of the systemic exposure to drug . In the studies presented it was calculated by the combined linear/log-linear trapezoidal rule and extrapolated to infinity.

Cmax, the maximum observed plasma concentration, and t max , the time at which it was observed . t'h' the apparent terminal elimination half-life of drug or metabolite, which was determined by log-linear regression of the terminal slope of the log plasma concentration-time curve.

Table 2. Mean (range) valuesof pharmacokinetic parameters for halofantrine following singleoral doses (250-1000 mg) in 23 subjects

Dose of halofantrine (n = subject numbers)

Cmax(l1mol/l) [mean (range)] tmax(h) [median (range)] t,,,,(h) [mean (range)] AUC(G-"')(fLmol h- I r ') [mean (95% confidence limits)]

250 mg(6) 0.20 (0.08--0.36) 6 (5- 12)

10.5 (4.29-17.1) 2.92 (0.94-4.92)

500 mg(6) 0.26 (0.08-0.66) 7.5 (~)

23.0 (I I.8-35.5) 4.50 (2.52-6.50)

750 mg(6) 0,44 (0.16-0.84) 6 (6-7) 20.9 (10.5-36.8) 5.94 (3.94-7.92)

1000 mg(5) 0.26 (0.12-0.50) 6 (5-6) 18.8 ( 10.6-28.1) 4.54 (2.56-6.54)

17

Human pharmacokinetics of halofantrine

Table 3. Mean (range) values of pharmacokinetic parameters for halofantrlne and its N.desbutyl· halofantrine metabolite after a single 500 mg dose and three 500 mg doses at 6 h intervals (n= 10)

Cm"" (fLmol/l)

[mean (range)] tmax(h)

[median (range)] t'h(h) [mean (range)] AUC(o_OQ)(ILmol h-Jr l ) [mean (95% confidence limits)]

Single-dose halofantrine

Metabolite

0.59 (0.36-1.31)

0.21 (0.10-0.42)

(3.11-9.84)

6 (6-8)

12 (6-32)

15

(0.62-0.82) 48

(9-17)

(32-56)

23.4 (9.44-41.8)

74.9

11.2

(5.78-32.1)

Results of pharmacokinetic studies A single study in patients (Boudreau, 1984) has limited data available on the third day following treatment and has not, therefore, been used in this review.

Absorption. The first rising-dose, safety and pharmacokinetic study (Fleckenstein, 1983) performed in a small number of subjects gave no indication of increased absorption over the dose range 750-2000 mg. A second study (Wareham et al., 1986) of doses between 250 mg and 1000 mg attempted to address the question of dose proportionality in a group comparative study more specifically. The results are presented in Table 2. There was an increase in the mean AUCca-.",) following 250, 500 and 750 mg doses, although the 95% confidence intervals were wide, and the increase was not proportional to dose. The A UCca-.OO) after a dose of 1000 mg was no greater than that after a 500 mg dose. There was statistical evidence of a difference between the 250 rng and 750 mg doses, but otherwise the large inter-subject variability made further conclusions difficult. However, the median tmax Was consistent at about 6 h.

(23.2-156) 22.5 (6.0-45.4)

Repeat-dose halofantrine 6.4

38.1 ( 14.0-80.5)

97.7 (50.6-138)

Metabolite 0.70

103

(62.0-218) 113 (70.1-209)

A study to evaluate the bioequivalence of three different formulations (Shmuklarsky, 1987) suggested that the extent of absorption from suspension was approximately 20% less than from tablets or capsules. However, due to the wide within- and between-subject variability the difference was not statistically significant. The value for C max was approximately 30% lower after administration of the suspension. However, the mean values for t milX were similar (between 6.2 hand 7.1 h) after administration of each formulation.

Metabolism andelimination. N-desbutylhalofantrine is the major metabolite of halofantrine. In a study to evaluate the effect of single 500 rng doses and three 500 mg doses at 6 h intervals (Wareham et al., 1988) the pharmacokinetics of both halofantrine and its metabolite were studied. The results are given in Table 3. The plasma concentration/time profiles from 0 to 168 h after a single 500 mg dose are presented in Figs 1 and 2 for halofantrine and the N-desbutyl metabolite, respectively. The single-dose data indicate that peak levels of metabolite are observed at about 12 h and the estimated

18

Halofantrine in the treatment of multldrug-resistant malaria

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HOURS POST TREATMENT Fig. I. Mean plasma concentrations of ha/ofantrine following a single 500 mg oral dose (n = 10subjects).

elimination half-life is about three days compared with an elimination half-life of about one day for halofantrine in this study. Following three 500 mg doses in the same subjects Cm,x and A UC for halofantrine increased by ll-fold and ninefold, respectively, ie. far greater than the approximate threefold increase expected. The increase in em,x for metabolite was about threefold, which is of the order expected based on the single-dose data but less than would be expected from the observed halofan-

trine plasma concentrations. em ax also occurred later than expected. There was an approximately fivefold increase in AUe for metabolite relative to the single-dose metabolite data. Elimination half-lives were greater than those derived from the single-dose data; the mean values were 38 hand 103 h for halofantrine and the N-desbutyl metabolite, respectively.

Discussion The limited pharrnacokinetic data available indicate wide inter-subject

19

Human pharmacokinetics of halofantrine

variability in the extent of absorption of halofantrine, although the time to maximum plasma concentration appears consistent at about 6 h. The study of dose proportionality was flawed in that this was not studied within subject using a balanced cross-over design, which would have addressed the problem of between-subject variability. Such a design would require washout periods between doses of at least five half-lives of the measurable metabolite. In the study of a repeat-dosing regi-

men, when three 500 mg doses were given at 6 h intervals, there was anunexpectedly large increase in plasma concentrations. This may have been due in part to enhanced absorption caused by the presence of food which was taken 2 h before the second and third doses. Similar food interactions are well documented. However, the effect of food on bioavailability is complex (Welling, 1984; Melander, 1978). The extent of this suspected interaction needs to be characterized. The relevance of such a

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HOURS POST TREATMENT Fig. 2. Mean plasma concentration ofN -desbutyl-halofantrine following a single500mg oral dose of ha/ofantrine hydrochloride (n = 10subjects).

20

Halo fantrine in the treatment of multldrug-reslstant malar ia

food interaction to the treatment of malaria is unknown . Initiation of treatment usually takes place in the fasting state , although subsequent treatment may follow food, albeit not of the relatively high pr otein and lipid content typical of the western diet , as used in the above study. Additionally , the data from the repeatdose study show that the in crease in Ndes but yl metabolite plasma concentrations following repeat dosing is not as large as that expected from the observed halofantrine plasma concentrations, and also the time to peak levels of metabolite wa s dela yed to 48 h (36 h following the final halofantrine dose ). These observations suggest that at the high pla sma concentrations of halofantrine observed in this study there may be saturation of metabolism . The higher plasma concentrations attained follow ing repeat dosing gave more quantifiable data points during the elimination phase and allowed gre ater accuracy in the determination of halofantrine elimination half-life (affected to an unknown extent if saturation of metabolism occurred) and that of Ndes butyl halofantrine . The calculation of the elimination half-life and A UCCO_co ) should ideall y be based on quantifiable data over a period of five half-li ves following drug administration. Since qu antifiable plasma levels were attained to

mu ch less th an this in mo st studies , as indicated in Figs I and 2, it is imp ortant that an assay with greater sensitivity be developed to substantiate the preliminary pharrnacokinetic data.

References Boudreau , E. F. (I 984) WRAIR Report : Phase III Clinical trial of halofanrrine in the treatment of Ialciparurn malaria, Chantaburi, Thailand, 1982-1 984 .

Fleckenstein, L. , Pamplin , C. L. and von Bredow, J. (1983 ) WRAIR Rep ort on antim alarial drug project experiment number 15: Pharmacokinetics and bioavailability of orally administered halofantrine (WR 171, 699.HC I) in health y volunteers. Lin , E. T. et al. (1985) WRAIR Report : Ion-paired liquid chromatographic meth od for the analysis of halolantrine (W R 171,669) and its put ative metabolite, WR 178,4 60, in blood and plasma. Melander , A. (I978) Influence of food on the bioavailability of drug s. Clin . P hannacohinet, 3, 337-3 5 1

Shrnuklarsky, M. J. at al. (1987 ) WRAIR Report: Th e comparative bioavailabitity of three oral formu lations of halofantrine hydr ochloride in healthy human subjects. Wareham, K . at al. (1986) SK&F Report on Protocol 102886/AOIIUK. Report of a study in healthy male su biccts to assess the pharmacokinetics and dose-proporti onaliry of single oral doses of halofantr ine (2501000 mg) . Wareham, K . et al. (1 988) SK&F Report: A study in healthy male su bjects to investigate the effect of multiple dosing on blood concentrations of halofantrine. Welling, P. G. (1984) Interaction affecting drug absorption. Clin. Pharmacokinet . 9, 404-434