Clinical Pharmacokinetic Considerations in the Treatment of Patients with Leprosy

Summary

On the basis of the efficacy of the available agents, the World Health Organization has recommended only 4 drugs for combined chemotherapy of leprosy: rifampicin, dapsone, clofazimine and ethionamide/prothionamide. Thiacetazone and isoniazid are also used to a lesser extent by some physicians. Pyrazinamide may find a place in treating ‘persister’ bacilli.

Dapsone is absorbed slowly after oral administration. Peak plasma drug concentration is reached at about 4 hours; absorption half-life is 1.1 hours; elimination half-life is about 30 hours. Oral availability is around 90%. Dapsone is approximately 70% protein-bound, while its monoacetylated metabolite is amost entirely bound. Dapsone crosses the placenta and is excreted into breast milk. It is metabolised via acetylation and N -hydroxylation, but acetylation polymorphism has no effect on dapsone handling by leprosy patients. Dapsone penetrates into sciatic nerves of experimental animals but its presence has not been demonstrated in Schwann cells.

Oral doses of rifampicin are rapidly and completely absorbed. The bioavailability is greater when the drug is given before meals; peak concentrations occur at 1 to 2 hours. 80 to 90% of rifampicin is bound to plasma proteins, and the drug is found in saliva, cerebrospinal fluid and breast milk. Its main metabolite, desacetyl rifampicin, also exhibits antimycobacterial activity in tuberculosis. Rifampicin induces its own metabolism, as well as that of dapsone and steroids. Absorption of dapsone and rifampicin is reported to be reduced in leprosy patients.

Clofazimine has been in use in leprosy treatment since 1960. In higher doses it exerts an anti-inflammatory action which is useful in treating leprosy patients in reaction. Oral absorption of the drug is slow and dose-dependent; faecal excretion also increases with dose. Single- and multiple-dose studies have shown a plasma half-life of around 10 days. Bioavailability of the drug is higher when given with food than when fasting; the peak plasma concentration occurs at 4 to 8 hours when the drug is administered with breakfast. After absorption, the drug is thought to circulate in protein-bound form, accounting for the fact that it is deposited in various tissues. Uneven distribution and prolonged retention in the tissues are special features of clofazimine metabolism. One unconjugated and 2 conjugated metabolites have been detected in urine, and the urinary excretion of both the parent compound and its metabolites is around 1% of the dose. Clofazimine crosses the placental barrier and is excreted into breast milk, but does not cross the blood-brain barrier. Small amounts of the drug are found in sebum and sweat.

The pharmacokinetic properties of ethionamide and prothionamide are similar in man. Both are absorbed rapidly and completely following oral administration. Peak plasma concentration of prothionamide occurs at around 18 minutes; plasma half-life is about 2 hours. The sulphoxide metabolite of the drug is active against Mycobacterium leprae.

The pharmacokinetics of thiacetazone, isoniazid and pyrazinamide are reviewed briefly. All 3 drugs are well absorbed after oral administration.

Haematological, dermatological and neurological effects and gastrointestinal symptoms are some of the side effects of the drugs reviewed. These may not pose serious problems at therapeutic dosages in leprosy, but the increased incidence of hepatotoxicity on combining rifampicin and ethionamide/prothionamide causes serious concern.

Rifampicin increases the excretion of dapsone, although this is not of therapeutic significance. Dapsone plus clofazimine reduces the absorption of rifampicin, while rifampicin plus dapsone does not affect absorption of clofazimine. Isoniazid treatment lowers the tissue concentration of clofazimine and increases its urinary excretion.