Lonafarnib

Lonafarnib is a disease modifying agent that prevents farnesylation, thereby reducing the accumulation of aberrant progerin and progerin-like proteins in the cell’s inner nuclear membrane. This results in maintaining cell integrity and normal function. The accumulation of progerin and progerin-like proteins in the cells within the walls of large blood vessels causes inflammation and fibrosis.

Absorption

Absolute bioavailability has not been assessed. Lonafarnib is absorbed via the oral route. The median time to maximum peak concentration (t_max) was 2 to 4 hours. Following multiple dose administration of lonafarnib (100 mg twice daily for 5 days) in healthy volunteers, the mean maximum peak concentration was 964 ng/mL observed at a median time of 4 hours (2 to 5 hours range).

In healthy volunteers, the exposure following a single oral dose of 75 mg lonafarnib taken as an intact capsule was compared to the exposure following a single oral dose of 75 mg lonafarnib capsule contents mixed with orange juice. When the capsule contents were mixed with orange juice the C_max of lonafarnib was reduced by 9% and the AUC was reduced by 8% as compared to when administered as an intact capsule.

In healthy volunteers, following a single oral dose of 100 mg lonafarnib, food decreased the absorption of lonafarnib and the relative oral bioavailability under fed conditions as compared to fasted conditions was 48% and 77% based on C_max and AUC, respectively. Multiple-dose administration of lonafarnib with food in healthy adult subjects did not have a significant effect on bioavailability and resulted in lower inter-subject variability (~16%).

In healthy volunteers, the accumulation ratio is estimated to be 4.46 for AUC_TAU/AUC_0-12 and 3.36 for C_max.

The intra-individual variability is 20.79% for C_max and 21.13% for AUC_TAU and the inter-individual variability is 36.92% for C_max and 50.75% for AUC_TAU.

Distribution

In vitro plasma protein binding of lonafarnib was ≥99% over the concentration range between 0.5 to 40.0 micrograms/mL. The blood-to-plasma ratio was 0.992 to 1.56.

Lonafarnib exhibits time-dependent pharmacokinetics. Comparing studies in healthy adult volunteers of single-dose 75 mg lonafarnib to 75 mg lonafarnib twice daily for 5 days shows the lonafarnib apparent volume of distribution is reduced by 60% (242 L and 97.4 L, respectively) following multiple dose lonafarnib for 5 days.

Biotransformation

Lonafarnib is extensively metabolised via hepatic means. Lonafarnib accounted for 50% to 57% of the profiled plasma radioactivity. Total plasma recovery for the two metabolites of interest: HM17 (15.1%) and HM21 (13.9%); therefore, a total of 79% to 86% of the plasma radioactivity was recovered. The common metabolic pathways included oxidation, dehydrogenation and combinations of these two processes. Most of the metabolites resulted from structural changes in the pendant piperidine ring region of lonafarnib.

HM21 is a pharmacologically active metabolite. Following oral administration of 100 mg lonafarnib twice daily for 5 days, HM21 has a peak plasma concentration of 94.8 ng/mL occurring after approximately 4 hours (range: 3 to 6), with an AUC_TAU of 864 ng·h/mL. Following oral administration of 75 mg lonafarnib twice daily for 5 days, HM21 has a peak plasma concentration of 82.1 ng/mL after approximately 3 hours (range: 3 to 5), with an AUC_TAU of 767 ng·h/mL.

In vitro metabolism studies indicate that CYP3A4 and CYP3A5 are mainly responsible for the oxidative metabolism of lonafarnib and that lonafarnib is an in vivo-sensitive CYP3A4 substrate.

Twenty-one metabolites were characterised/identified in urine and faeces. No single uncharacterised metabolite represented greater than 5% of the dose.

Transporters

Based on the in vitro data, lonafarnib is most likely a substrate of P-glycoprotein and not a substrate of BCRP, OCT1, OATP1B1 and OATP1B3.

Elimination

A ¹⁴C-absorption, metabolism and excretion trial conducted in healthy volunteers following singledose administration of lonafarnib revealed that drug-derived radioactivity was primarily excreted via the faeces. Mean cumulative excretion of radioactivity was 61% in faeces and less than 1% in urine up to 24 hours post-dose (total recovery was ~62% in the mass balance study).

Lonafarnib exhibits time-dependent pharmacokinetics. Comparing studies in healthy adult volunteers of single-dose 75 mg lonafarnib to 75 mg lonafarnib twice daily for 5 days shows lonafarnib clearance was reduced by 75% (48.2 L/h and 12.1 L/h, respectively) and the t_1/2 increased by 60% (3.5 h versus 5.6 h, respectively) following multiple dose lonafarnib for 5 days.

Special populations

Hepatic impairment

Lonafarnib has not been studied in patients with hepatic impairment. Co-administration of a single oral dose of 50 mg lonafarnib (combined with a single oral dose of 100 mg ritonavir) in mild and moderate hepatically impaired subjects showed similar lonafarnib exposures relative to the matched normal control group (normal hepatic function). These results indicate no dose adjustments are warranted in patients with mild or moderate hepatic impairment. Lonafarnib is contraindicated in patients with severe hepatic impairment due to the predicted safety issue of decompensation due to the risk of diarrhoea. Lonafarnib (and most likely HM21) is extensively metabolised in the liver. Therefore, decreased hepatic function will most likely lead to an increase in exposure to lonafarnib (effect on HM21 is unknown).

Renal impairment

Lonafarnib has not been studied in patients with renal impairment. Lonafarnib and HM21 are only excreted to a limited extent via urine. Therefore, it is not expected that renal impairment will affect the exposure to lonafarnib and HM21.

Gender

In healthy volunteers, following a single oral dose of 100 mg lonafarnib, the pharmacokinetic data suggest lonafarnib exposures (AUC_0-inf) are higher in female subjects (44% higher) as compared to male subjects. Gender had less of an effect (26%) on the C_max as compared with AUC_0-inf.

Age

In healthy volunteers, following a single oral dose of 100 mg lonafarnib, the pharmacokinetic data show lonafarnib exposures (AUC_0-inf) are higher in elderly subjects (59% higher in those aged 65 years or older) as compared to younger subjects aged 18 to 45 years. Age had less of an effect (27%) on the C_max as compared with AUC_0-inf.

Lonafarnib had no effects on QT or QTc interval in guinea pigs and no electrocardiogram (ECG) changes were observed in monkeys. Lonafarnib produced modest and isolated effects on the QT interval of ECG in rats at estimated exposures similar to that seen in humans.

A no-observed-adverse-effect level (NOAEL) could not be established in studies of up to 1-year duration in monkeys. Systemic toxicity was observed in 3-month and 1-year toxicity studies in rats and monkeys following repeated oral administration of lonafarnib at doses ≥30 and ≥10 mg/kg/day, respectively, corresponding to exposures lower than what is seen in patients. Toxicity findings included bone marrow suppression, testicular toxicity and lymphoid toxicity in rats and monkeys; kidney changes in rats(vacuolisation, mineralisation and necrosis of the inner renal medulla); and diarrhoea and electroretinographic changes in monkeys. In a 3-month toxicity study in monkeys, acute morbidity due to haemorrhage in multiple organs was observed in a small number of monkeys administered 60 mg/kg/day, corresponding to exposuressimilar to that seen in humans (at 150 mg/m² twice daily). In toxicity studies in monkeys, ocular findings of single cell necrosis of retinal photoreceptors were observed at ≥40 mg/kg/day. In a 3-month follow up study, changes in electroretinography were noted at ≥15 mg/kg/day, including substantial changesin scotopic amplitudes at 60 mg/kg/day indicating perturbation of rod cells and impairment of night vision. The NOAEL for ocular toxicity for lonafarnib was considered to be 20 mg/kg/day, corresponding to exposures similar to those seen in humans (at 150 mg/m² twice daily).

Lonafarnib increased pre- and post-implantation loss and decreased the number of live foetusesin female rats at doses ≥30 mg/kg/day. Decreased maternal body weight and lower foetal body weights were also observed at this dose level. The NOAEL for maternal toxicity and F1 litters was considered 10 mg/kg/day, with an estimated exposure level lower than what is seen in humans at 150 mg/m² twice daily.

Reproductive organ toxicity was observed in male rats and monkeys, including lower testicular and epididymal weight, aspermia, altered spermatogenesis and spermatogonial debris in male rats at ≥90 mg/kg/day, and lower testes weights in male monkeys at the lowest tested dose 10 mg/kg/day. The NOAEL or the lowest tested dose regarding these effects corresponds to exposure levels lower than what is seen in humans at 150 mg/m² twice daily.

Lonafarnib demonstrated teratogenic potential at clinically relevant exposures in rabbitsin the absence of maternal toxicity, with increased incidence of malformations and variations in foetal skeletal development observed at the lowest tested dose 10 mg/kg/day, corresponding to an exposure level lower than what is seen in humans at 150 mg/m² twice daily. Maternal toxicity was observed at ≥40 mg/kg/day and both maternal and embryofoetal toxicity, including abortion, discoloured urine, body weight loss, increased post-implantation loss and decreased foetal body weight, were observed at 120 mg/kg/day, corresponding to exposures greater than those seen in humans (~2- and 25-times the human exposure at 150 mg/m² twice daily, respectively). In rats, lonafarnib had no adverse effects on F1 and F2 generationsin a pre- and post-natal development study. Lonafarnib is excreted in milk following oral administration in lactating rats, with a mean milk to plasma concentration ratio of 1.5 at 12 hours.

Overall, lonafarnib does not represent a genotoxic concern based on results of in vitro tests, including bacterial reverse mutation assays and a chromosome aberration assay using human peripheral blood lymphocytes. In the in vivo mouse bone micronucleus assay, lonafarnib was not genotoxic at doses up to 50 and 60 mg/kg/day (intraperitoneal injection) in male and female mice, respectively. However, these dose levels are lower than the clinical relevant dose.

The carcinogenic potential of lonafarnib has not been studied.