Terbinafine

Terbinafine is an allylamine which has a broad spectrum of antifungal activity. At low concentrations terbinafine is fungicidal against dermatophytes, moulds and certain dimorphic fungi. The activity versus yeasts is fungicidal or fungistatic depending on the species.

Terbinafine interferes specifically with fungal sterol biosynthesis at an early step. This leads to a deficiency in ergosterol and to an intracellular accumulation of squalene, resulting in fungal cell death. Terbinafine acts by inhibition of squalene epoxidase in the fungal cell membrane.

The enzyme squalene epoxidase is not linked to the cytochrome P-450 system. Terbinafine does not influence the metabolism of hormones or other drugs.

Terbinafine has an antimycotic effect on fungal infections of the skin caused by dermatophytes such as Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum), Microsporum canis and Epdermophyton floccosum. At low concentrations terbinafine has a fungicidal effect against dermatophytes and moulds. Its activity against yeasts is fungicidal (e.g. Pityrosporum orbiculare or Malassezia furfur) or fungistatic, depending on the species.

The following table outlines the range of minimum inhibitory concentrations (MIC) against the dermatophytes.

When given orally, the active substance concentrates in skin, hair and nails at levels associated with fungicidal activity. Measurable concentrations of the active substance are still evident 15–20 days after cessation of treatment.

Terbinafine tablets exhibits poor efficacy against many yeasts of the Candida species.

Terbinafine tablets in contrast to locally administered terbinafine tablets treatment, has no effect in the treatment of Pityriasis (Tinea) versicolor.

Absorption

Following oral administration, terbinafine is well absorbed (>70%) and the absolute bioavailability of terbinafine from tablets as a result of first-pass metabolism is approximately 50%. A single oral dose of 250mg terbinafine resulted in mean peak plasma concentrations of 1.30μg/ml within 1.5 hours after administration. Plasma concentrations decline in a triphasic manor, with a terminal half-life of 16.5 days. At 28 days, when around 70% steady state levels have been achieved, peak concentrations of terbinafine was on average 25% higher and plasma AUC increased by a factor of 2.3 when compared to single dose administration. From the increase in plasma AUC an effective half-life of ~30 hours can be calculated. The bioavailability of terbinafine is moderately affected by food (increase in the AUC of less than 20%), but not sufficiently to require dose adjustments.

Less than 5% of the dose is absorbed after topical application to humans: systemic exposure is thus very low.

Distribution

Terbinafine tablets binds strongly to plasma proteins (99%).

It rapidly diffuses through the dermis and concentrates in the lipophilic stratum corneum. Terbinafine is also secreted in sebum, thus achieving high concentrations in hair follicles, hair and sebum rich skins. There is also evidence that terbinafine is distributed into the nail plate within the first few weeks of commencing therapy.

Biotransformation

Terbinafine is metabolised rapidly and extensively by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. Biotransformation results in metabolites with no antifungal activity, which are excreted predominantly in the urine.

Elimination

The elimination half-life is 17 hours. There is no evidence of accumulation in the plasma.

No age-dependent changes in pharmacokinetics have been observed but the elimination rate may be reduced in patients with renal or hepatic impairment, resulting in higher blood levels of terbinafine.

In patients with pre-existing mild to severe hepatic impairment, single dose pharmacokinetic studies have shown that the clearance of terbinafine tablets can be reduced by 50%.

The bioavailability of terbinafine tablets is only slightly affected by food, and therefore a dose adjustment is not necessary.

Single dose pharmacokinetic studies in patients with renal impairment (creatinine clearance <50 ml/min) or with pre-existing liver disease have shown that clearance of terbinafine may be reduced by about 50%.

The approximate LD₅₀ value of Terbinafine tablets is over 4 g/kg in both mice and rats.

In long-term studies (up to 1 year) in rats and dogs no marked toxic effects were seen in either species up to oral doses of about 100mg/kg a day. At high oral doses, the liver and possibly also the kidneys were identified as potential target organs.

In a two-year oral carcinogenicity study in mice, no neoplastic or other abnormal findings attributable to treatment were made up to doses of 130 (males) and 156 (females) mg/kg a day. In a two-year oral carcinogenicity study in rats, an increased incidence of liver tumours was observed in males at the highest dosage level of 69mg/kg a day. The changes which may be associated with peroxisome proliferation have been shown to be species-specific since they were not seen in the carcinogenicity study in mice, dogs or monkeys.

During high-dose studies in monkeys, refractile irregularities were observed in the retina at the higher doses (non-toxic effect level 50mg/kg). These irregularities were associated with the presence of a terbinafine metabolite in ocular tissue and disappeared after drug discontinuation. They were not associated with histological changes.

A standard battery of in vitro and in vivo genotoxicity tests revealed no evidence of mutagenic or clastogenic potential.

No adverse effects on fertility or other reproduction parameters were observed in studies in rats or rabbits.