Pharmacokinetics and drug interactions of newer anti -leprosy drugs

During the last two decades, chemotherapy of leprosy has undergone a remarkable change. The wide-spread emergence of dapsone-resistant strains of M leprae in lepromatous leprosy patients on dapsone monotherapy has forced leprologists all over the world to develop suitable multidrug therapeutic regimens. The drugs which are already in use as part of well tried MDT regimens are dapsone, rifampicin, clofazimine and thioamides. Some of the newer drugs whick are being tried as part of new MDT regimens are clarithromycin (a macrolide), minocycline (a tetracycline) and pefloxacin and ofloxacin (fluoroquinolones). The other drugs with antimycobacterial efficacy are ansamycins (rifabutin, rifapentine, isobutylpiperizinyl rifampicin S.V., fusidic acid, combination of amoxicillin with potassium clavulanate, brodimoprim, thiacetazone and desoxyfructoserotonin.

Brief review of pharmacokinetics of drugs already in use

The pharmacokinetics and interactions of dapsone, rifampicin, clofazimine and prothionamide / ethionamide have been reviewed extensively.[1][2][3][4]5]

Dapsone (diamino-diphenyl sulphone, DDS) is absorbed slowly after oral administration. Peak plasma drug concentrations are reached at about 4 hours. The elimination half-life is around 30 hours. Oral availability is about 90%. Dapsone is about 70% protein bound while its monoacetylated matabolite MADDS is almost entirely bound. At steady state which may be reached after 7-14 daily doses of 100mg of dapsone, plasma drug concentrations at any time will be about 150 times, greater than the minimum inhibitory concentration (MIC) for M leprae in blood (as determined on mice). Dapsone penetrates into sciatic nerves of experimental animal but its presence has not been demonstrated in Schwann cells. Simultaneous administration of rifampicin decreases the half-life of dapsone by a factor of about 2 and lowers its plasma, skin and nerve concentrations considerably. However, the lowered dapsone levels in blood are still above the MIC of dapsone for M leprae. Pyrimethamine lowers the peak serum concentrations of dapsone.

Oral doses of rifampicin are rapidly and completely absorbed and the bioavailability of the drug is greater when given before meals. The peak plasma concentrations occur at 1-2 hours. Rifampicin is bound to plasma proteins to about 80 to 90%. 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 several drugs including dapsone and steroids.

Oral absorption of clofazimine is slow and dose-dependent. The faecal excretion of the drug increases with dose. Single and multiple-doses studies have shown a plasma half-life of around 10 days. Bioavailability of the drug is more when given with food. The peak plasma concentration occurs at 4 to 8 hours after the drug is given with breakfast. After absorption the drug is thought to circulate in protein-bound form. Slow and uneven distribution and prolonged retention in the tissues are special features of clofazimine metabolism. Urinary excretion of clofazimine and its metabolites is around 1% of the dose. Clofazimine crosses placental barrier and is excreted into breast milk in significant amounts. The drug does not cross the blood-brain barrier. Small amounts are excreted in sebum and sweat.

The pharmacokinetic properties of ethionamide and prothionamide are similar in man. Both the drugs are absorbed rapidly and completely following oral administration. Peak plasma concentrations of prothionamide occur at around 18 minutes; the plasma half-life is about 2 hours. The sulphoxide metabolite of the drug is also active against M leprae. There is an increased incidence of hepatotoxicity on combining rifampicin and thioamide and this is a matter of serious concern.

Pharmacokinetics of newer antileprosy drugs

i. Fluoroquinolones: This group of compounds exert their antimycobacterial effect by inhibiting DNA gyrase (an enzyme which is not affected by any other therapeutic agents in use). Of several fluoroquinolones, pefloxacin, ofloxacin, norfloxacin, ciprofloxacin and enoxacin have been most extensively studied for their activities against both gram-negative and gram-positive bacteria.[6] The experimental studies have shown that ciprofloxacin is inactive against M leprae infection in mice.[7] This could be, perhaps, due to its unfavourable pharmacokinetic properties. Although pefloxacin and ofloxacin are found to be active against M leprae the latter completely prevented the growth and multiplication of M leprae in mice at daily doses of 50 nag/kg while the former required a daily dose of 150 mg/kg.[8] Fluoroquinolones, as a whole, are absorbed very well from the gastrointestinal tract. The absorption of ciprofloxacin is reported to be delayed by food.[9] After a single oral dose, peak serum levels are obtained with ofloxacin and also the bioavailability of ofloxacin is the highest.[10] The elimination half-lives of pefloxacin and ofloxacin are in the range of 10-12 hours and 5-8 hours respectively. Binding of fluoroquinolones to serum protein is very low (that of ofloxacin is about 25%) and high proportion of fluoroquinolones in the blood is available in free form. All fluoroquinolones other than ofloxacin, are metabolised in the liver and the metabolites have antibacterial activity.[11]

To summarise the pharmacokinetic profile of ofloxacin, the drug given at a daily dose of 400 mg is well absorbed, reaching a peak serum concentration of 2.9 μg/ml after 2 hours and has a serum half-life of 7 hours. It is excreted mainly unchanged by the kidneys. Reported side effects are nausea, diarrhoea and other gastrointestinal complaints and variety of central nervous system complaints including insomnia, headache, dizziness and hallucinations.[7] Hypersensitivity reactions to ofloxacin are almost similar to those of other quinolones. These are in the form of mild non-specific skin rashes. Since they are usually mild, they do not require ofloxacin stoppage.[12]

ii. Clarithromycin Clarithromycin is a semisynthetic macrolide antibiotic, structurally related to erythromycin. It has a more favourable pharmacokinetic profile than erythromycin. Administered in a dosage of 500 mg daily to leprosy patients, the drug is reported to kill 99 percent of M leprae by 58 days.[7] Clarithromycin is rapidly absorbed from the gastrointestinal tract and its systemic availability is reduced (about 55%) because of its first-pass metabolism. It undergoes rapid biodegradation to get converted into active 14-hydroxy (R) metabolite which is mainly excreted in the urine along with the parent compound. The peak serum concentration of clarithromycin and its 14-hydroxy metabolite obtainable with single oral doses of the drug are dose proportional. The peak drug concentration of 1μ g/ml is reached 1-4 hours after a 500mg dose.

The mean elimination half-life is 6-7 hours. Without multiple doses, steady state concentrations are attained after 5 doses. The presence of food appears to have no clinically significant effect on clarithromycin pharmacokinetics. However, it is of interest to note that food intake immediately before administration of the drug increases its bioavailability by about 25%.[13] Being lipid soluble, clarithromycin is extensively distributed both in body fluids and tissues. Following repeated oral doses of 250 mg or 500 mg, clarithromycin presented tissue concentrations (tonsils, skin, nasal mucosa, lung) markedly higher than those in serum. [13,14] A reduction in urinary clearance in the elderly and in patients with renal impairment is associated with an increase in area under the plasma concentration-time curve, peak plasma concentration and elimination half-life. Nausea, diarrhoea, dyspepsia, abdominal pain and headache are the most frequently reported adverse events following clarithromycin therapy. Most of these effects are considered mild or moderate and unrelated to age.[13]

The concurrent administration of rifampicin is reported to decrease serum clarithromycin concentration by 80%. However, the concentration of microbiologically active 14-hydroxy metabolite remained unchanged in serum.[7]

Clarithromycin exerts its antimycobacterial effect by linking to the 50 ribosomal sub-unit, thus inhibiting bacterial protein synthesis.

iii. Minocycline Minocycline is the only tetracycline that demonstrates significant activity against M leprae, perhaps due to its liopophilicity which permits it to penetrate the mycobacterial cell wall. [15,7] The standard dose is 100 mg daily at which the peak serum concentrations of 2-4 μg/ml (mean 1.84 μg/ml) are obtained within 2 hours of administration of 0.2 μg/ml for M leprae. The reported elimination half-life is 11-23 hours. The drug is bactericidal against M leprae, but less powerful than rifampicin in exerting bactericidal effect.[7] Like other tet-racyclines, minocycline exerts its antibacterial action by binding reversibly at the 30 s sub-unit of the ribosome, blocking the binding of aminoacyl transfer RNA to the messenger RNA ribosomal complex, thereby inhibiting protein biosynthesis. Discolouration of teeth in infants and children, occasional pigmentation of the skin and mucous membrane, various gastrointestinal complaints, and central nervous system toxicity are some of the side effects of minocycline therapy. There has been a report pertaining to the occurrence of hepatitis or systemic lupus in patients treated with minocycline for acne.[16]

iv. Ansamycins For the last twenty years or so, efforts have been made to synthesize/produce analogue or derivatives of rifampicin which would be more effective than rifampicin itself. These new derivatives, together, have been called ansamyeins. The first ansamycin found effective was Rifabutin or LM 427. This drug was shown to be more potent than rifampicin against M tuberculosis and was also reported to be effective against rifampicin-resistant strains of M tuberculosis in mice. Likewise, it was found to be effective against M leprae from newly diagnosed lepromatous leprosy patients, the minimal inhibitory concentration being much lower than that for rifampicin.[17] R-76-1 (isobutylpiperazinyl rifampicin SV) and DL 473 (Rifapentine) have been reported to be more effective in M leprae murium cultures and against M leprae in mice.[18] A longer half-life (of rifapentine) together with the greater intrinsic activity (rifabutin and R-76-1) against M leprae makes them very attractive as components of intermittent therapy. However, their utility in MDT remains unclear as of today the action of these ansamycins against rifampicin-resistant strains of M leprae has not been confirmed.[12] Rifabutin (LM 427) is a spiropiperidyl derivative of rifamycin S. It is much more lipid soluble than rifampicin. It has relatively low oral bioavailability of about 20%, after single dose administration. The peak blood concentrations are reached 2.5 - 3 hours after oral administration of a capsule or oral solution of the drug. The peak blood concentrations of rifabutin are low in comparison to those levels with equivalent doses of rifampicin. With long term administraion, rifabutin induces its own metabolism and the metabolism of some other drugs. The serum half-life of rifabutin is long (45 hours), but average plasma concentration remains relatively low after repeated administration of standard doses due to very large volume of distribution (Vd) of the drug. In vitro, rifabutin is more active against M avium-M intracellulare complex and atleast as active against M tuberculosis as rifampicin. But due to its lower concentration at equivalent doses, rifabutin′s action in vivo is less apparent. Adverse effects are unusual at the recommended oral doses of 300 nag/day.[19]

Other drugs with anti-M leprae activity

The other drugs that have been studied for their anti M leprae activity are fusidic acid, combination of amoxicillin with potassium clavulanate, brodimoprim, thiacetazone and desoxy fructoserotonin. Except fusidic acid, all others are much less potent against M leprae. They are merely bacteriostatic and so there is only little reason to use any of these bacteriostatic drugs at the time when large number of much more potent drugs are available for inclusion in short course therapeutic regimens required.