Ivacaftor

Ivacaftor is a potentiator of the CFTR protein, i.e., in vitro ivacaftor increases CFTR channel gating to enhance chloride transport in specified gating mutations with reduced channel-open probability compared to normal CFTR. Ivacaftor also potentiated the channel-open probability of R117H-CFTR, which has both low channel-open probability (gating) and reduced channel current amplitude (conductance). The G970R mutation causes a splicing defect resulting in little-to-no CFTR protein at the cell surface which may explain the results observed in subjects with this mutation in study 5.

In vitro responses seen in single channel patch clamp experiments using membrane patches from rodent cells expressing mutant CFTR forms do not necessarily correspond to in vivo pharmacodynamic response (e.g., sweat chloride) or clinical benefit. The exact mechanism leading ivacaftor to potentiate the gating activity of normal and some mutant CFTR forms in this system has not been completely elucidated.

Pharmacodynamic effects

Ivacaftor as monotherapy

In studies 1 and 2 in patients with the G551D mutation in one allele of the CFTR gene, ivacaftor led to rapid (15 days), substantial (the mean change in sweat chloride from baseline through week 24 was -48 mmol/L [95% CI -51, -45] and -54 mmol/L [95% CI -62, -47], respectively) and sustained (through 48 weeks) reductions in sweat chloride concentration.

In study 5, part 1 in patients who had a non-G551D gating mutation in the CFTR gene, treatment with ivacaftor led to a rapid (15 days) and substantial mean change from baseline in sweat chloride of -49 mmol/L (95% CI -57, 41) through 8 weeks of treatment. However, in patients with the G970RCFTR mutation, the mean (SD) absolute change in sweat chloride at week 8 was -6.25 (6.55) mmol/L. Similar results to part 1 were seen in part 2 of the study. At the 4-week follow-up visit (4 weeks after dosing with ivacaftor ended), mean sweat chloride values for each group were trending to pre-treatment levels.

In study 6 in patients aged 6 years or older with CF who had an R117H mutation in the CFTR gene, the treatment difference in mean change in sweat chloride from baseline through 24 weeks of treatment was -24 mmol/L (95% CI -28, -20). In subgroup analyses by age, the treatment difference was -21.87 mmol/L (95% CI: -26.46, -17.28) in patients aged 18 years or older, and -27.63 mmol/L (95% CI: -37.16, -18.10) in patients aged 6-11 years. Two patients 12 to 17 years of age were enrolled in this study.

Ivacaftor in a combination regimen with tezacaftor/ivacaftor

In patients homozygous for the F508del mutation, the treatment difference between ivacaftor in combination with tezacaftor/ivacaftor and placebo in mean absolute change from baseline in sweat chloride through week 24, was -10.1 mmol/L (95% CI: -11.4, -8.8).

In patients heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity, the treatment difference in mean absolute change from baseline in sweat chloride through week 8 was -9.5 mmol/L (95% CI: -11.7, -7.3) between tezacaftor/ivacaftor and placebo, and -4.5 mmol/L (95% CI: -6.7, -2.3) between ivacaftor and placebo.

In patients aged 6 to less than 12 years who were homozygous or heterozygous for the F508del mutation and a second mutation associated with residual CFTR activity, mean within-group absolute change in sweat chloride from baseline at week 8 was -12.3 mmol/L (95% CI: -15.3, -9.3) in the tezacaftor/ivacaftor group.

Ivacaftor in a combination regimen with ivacaftor/tezacaftor/elexacaftor

In patients with an F508del mutation on one allele and a mutation on the second allele that predicts either no production of a CFTR protein or a CFTR protein that does not transport chloride and is not responsive to ivacaftor and tezacaftor/ivacaftor (minimal function mutation) in vitro, the treatment difference of ivacaftor/tezacaftor/elexacaftor compared to placebo for mean absolute change in sweat chloride from baseline through week 24 was -41.8 mmol/L (95% CI: -44.4, -39.3).

In patients homozygous for the F508del mutation, the treatment difference of ivacaftor/tezacaftor/elexacaftor compared to tezacaftor/ivacaftor for mean absolute change in sweat chloride from baseline at week 4 was -45.1 mmol/L (95% CI: -50.1, -40.1).

In patients heterozygous for the F508del mutation and a mutation on the second allele with a gating defect or residual CFTR activity, the treatment difference of ivacaftor/tezacaftor/elexacaftor compared to the control group (ivacaftor monotherapy group plus tezacaftor/ivacaftor group) for mean absolute change in sweat chloride from baseline through week 8 was -23.1 mmol/L (95% CI: -26.1, -20.1).

In patients aged 6 to less than 12 years, homozygous for the F508del mutation or heterozygous for the F508del mutation and a minimal function mutation, the mean absolute change in sweat chloride from baseline (n=62) through week 24 (n=60) was -60.9 mmol/L (95% CI: -63.7, -58.2)*. The mean absolute change in sweat chloride from baseline through week 12 (n=59) was -58.6 mmol/L (95% CI: -61.1, -56.1).

^* Not all participants included in the analyses had data available for all follow-up visits, especially from week 16 onwards. The ability to collect data at week 24 was hampered by the COVID-19 pandemic. Week 12 data were less impacted by the pandemic.

The pharmacokinetics of ivacaftor are similar between healthy adult volunteers and patients with CF.

After oral administration of a single 150 mg dose to healthy volunteers in a fed state, the mean (± SD) for AUC and C_max were 10600 (5260) ng*hr/mL and 768 (233) ng/mL, respectively. After every 12-hour dosing, steady-state plasma concentrations of ivacaftor were reached by days 3 to 5, with an accumulation ratio ranging from 2.2 to 2.9.

Absorption

Following multiple oral dose administrations of ivacaftor, the exposure of ivacaftor generally increased with dose from 25 mg every 12 hours to 450 mg every 12 hours. When given with fatcontaining food, the exposure of ivacaftor increased approximately 2.5- to 4-fold. When coadministered with tezacaftor and elexacaftor, the increase in AUC was similar (approximately 3-fold and 2.5-to 4-fold respectively). Therefore, ivacaftor, administered as monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, should be administered with fat-containing food. The median (range) t_max is approximately 4.0 (3.0; 6.0) hours in the fed state.

Ivacaftor granules (2 × 75 mg sachets) had similar bioavailability as the 150 mg tablet when given with fat-containing food to healthy adult subjects. The geometric least squares mean ratio (90% CI) for the granules relative to tablets was 0.951 (0.839, 1.08) for AUC_0-∞ and 0.918 (0.750, 1.12) for C_max. The effect of food on ivacaftor absorption is similar for both formulations, i.e., tablets and granules.

Distribution

Ivacaftor is approximately 99% bound to plasma proteins, primarily to alpha 1-acid glycoprotein and albumin. Ivacaftor does not bind to human red blood cells. After oral administration of ivacaftor150 mg every 12 hours for 7 days in healthy volunteers in a fed state, the mean (± SD) apparent volume of distribution was 353 L (122).

Biotransformation

Ivacaftor is extensively metabolised in humans. In vitro and in vivo data indicate that ivacaftor is primarily metabolised by CYP3A. M1 and M6 are the two major metabolites of ivacaftor in humans. M1 has approximately one-sixth the potency of ivacaftor and is considered pharmacologically active. M6 has less than one-fiftieth the potency of ivacaftor and is not considered pharmacologically active.

The effect of the CYP3A4*22 heterozygous genotype on ivacaftor, tezacaftor, and elexacaftor exposure is consistent with the effect of co-administration of a weak CYP3A4 inhibitor, which is not clinically relevant. No dose-adjustment of ivacaftor, tezacaftor, or elexacaftor is considered necessary. The effect in CYP3A4*22 homozygous genotype patients is expected to be stronger. However, no data are available for such patients.

Elimination

Following oral administration in healthy volunteers, the majority of ivacaftor (87.8%) was eliminated in the faeces after metabolic conversion. The major metabolites M1 and M6 accounted for approximately 65% of the total dose eliminated with 22% as M1 and 43% as M6. There was negligible urinary excretion of ivacaftor as unchanged parent. The apparent terminal half-life was approximately 12 hours following a single dose in the fed state. The apparent clearance (CL/F) of ivacaftor was similar for healthy subjects and patients with CF. The mean (± SD) CL/F for a single 150 mg dose was 17.3 (8.4) L/hr in healthy subjects.

Linearity/non-linearity

The pharmacokinetics of ivacaftor are generally linear with respect to time or dose ranging from 25 mg to 250 mg.

Special populations

Hepatic impairment

Following a single dose of 150 mg of ivacaftor, adult subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7 to 9) had similar ivacaftor C_max (mean [± SD] of 735 ³³¹ ng/mL) but an approximately two-fold increase in ivacaftor AUC_0-∞ (mean [± SD] of 16800 ⁶¹⁴⁰ ng*hr/mL) compared with healthy subjects matched for demographics. Simulations for predicting the steady-state exposure of ivacaftor showed that by reducing the dosage from 150 mg q12h to 150 mg once daily, adults with moderate hepatic impairment would have comparable steady-state C_min values as those obtained with a dose of 150 mg q12h in adults without hepatic impairment.

In subjects with moderately impaired hepatic function (Child Pugh Class B, score 7 to 9), ivacaftor AUC increased approximately by 50% following multiple doses for 10 days of either tezacaftor and ivacaftor or of ivacaftor, tezacaftor and elexacaftor.

The impact of severe hepatic impairment (Child Pugh Class C, score 10 to15) on the pharmacokinetics of ivacaftor as monotherapy or in a combination regimen with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor has not been studied. The magnitude of increase in exposure in these patients is unknown but is expected to be higher than that observed in patients with moderate hepatic impairment.

Renal impairment

Pharmacokinetic studies have not been performed with ivacaftor in patients with renal impairment, either as monotherapy or in a combination regimen with tezacaftor/ivacaftor or with ivacaftor/tezacaftor/elexacaftor. In a human pharmacokinetic study with ivacaftor monotherapy, there was minimal elimination of ivacaftor and its metabolites in urine (only 6.6% of total radioactivity was recovered in the urine). There was negligible urinary excretion of ivacaftor as unchanged parent (less than 0.01% following a single oral dose of 500 mg).

No dose adjustments are recommended for mild and moderate renal impairment. Caution is recommended when administering ivacaftor, either as monotherapy or in a combination with tezacaftor/ivacaftor or with ivacaftor/tezacaftor/elexacaftor, to patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min) or end-stage renal disease.

Race

Race had no clinically meaningful effect on the PK of ivacaftor in white (n=379) and non-white (n=29) patients based on a population PK analysis.

Gender

The pharmacokinetic parameters of ivacaftor, either as monotherapy or in combination with tezacaftor/ivacaftor or ivacaftor/tezacaftor/elexacaftor, are similar in males and females.

Elderly

Clinical studies of ivacaftor as monotherapy, or in a combination regimen with ivacaftor/tezacaftor/elexacaftor did not include sufficient numbers of patients aged 65 years and older to determine whether pharmacokinetic parameters are similar or not to those in younger adults.

The pharmacokinetic parameters of ivacaftor in combination with tezacaftor in the elderly patients (65-72 years) are comparable to those in younger adults.

Paediatric population

Predicted ivacaftor exposure based on observed ivacaftor concentrations in phase 2 and 3 studies as determined using population PK analysis is presented by age group in the following table.

Mean (SD) ivacaftor exposure by age group:

^* Values based on data from a single patient; standard deviation not reported.
^† Exposures in 6- to 11-year-olds are predictions based on simulations from the population PK model using data obtained for this age group.

Ivacaftor exposure in combination with tezacaftor and with tezacaftor/elexacaftor is presented in the following table.

Mean (SD) ivacaftor exposure when used in combination, by age group:

^* Exposures in ≥30 kg to <40 kg weight range are predictions derived from the population PK model.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Pregnancy and fertility

Ivacaftor was associated with slight decreases of the seminal vesicle weights, a decrease of overall fertility index and number of pregnancies in females mated with treated males and significant reductions in number of corpora lutea and implantation sites with subsequent reductions in the average litter size and average number of viable embryos per litter in treated females. The No-Observed-Adverse-Effect-Level (NOAEL) for fertility findings provides an exposure level of approximately 4 times the systemic exposure of ivacaftor and its metabolites when administered as ivacaftor monotherapy in adult humans at the maximum recommended human dose (MRHD). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

Peri- and post-natal development

Ivacaftor decreased survival and lactation indices and caused a reduction in pup body weights. The NOAEL for viability and growth in the offspring provides an exposure level of approximately 3 times the systemic exposure of ivacaftor and its metabolites when administered as ivacaftor monotherapy in adult humans at the MRHD.

Juvenile animal studies

Findings of cataracts were observed in juvenile rats dosed from postnatal day 7 through 35 at ivacaftor exposure levels of 0.22 times the MRHD based on systemic exposure of ivacaftor and its metabolites when administered as ivacaftor monotherapy. This finding has not been observed in foetuses derived from rat dams treated with ivacaftor on gestation days 7 to 17, in rat pups exposed to ivacaftor through milk ingestion up to postnatal day 20, in 7-week old rats, nor in 3.5 to 5-month old dogs treated with ivacaftor. The potential relevance of these findings in humans is unknown.