tafamidis: prescribing information – dosing, contraindications, interactions, side effects

Vyndaqel is indicated for the treatment of transthyretin amyloidosis in adult patients with stage 1 symptomatic polyneuropathy to delay peripheral neurologic impairment.

Vyndaqel is indicated for the treatment of wild-type or hereditary transthyretin amyloidosis in adult patients with cardiomyopathy (ATTR-CM).

Vyndaqel is indicated for the treatment of wild-type transthyretin amyloidosis in adult patients with cardiomyopathy (ATTRwt-CM).

Treatment should be initiated under the supervision of a physician knowledgeable in the management of patients with transthyretin amyloid polyneuropathy (ATTR-PN).

Posology

The recommended dose of tafamidis meglumine is 20 mg orally once daily.

Tafamidis and tafamidis meglumine are not interchangeable on a per mg basis.

If vomiting occurs after dosing, and the intact Vyndaqel capsule is identified, then an additional dose of Vyndaqel should be administered if possible. If no capsule is identified, then no additional dose is necessary, with resumption of dosing the next day as usual.

Special populations

Elderly

No dosage adjustment is required for elderly patients (≥ 65 years) (see section 5.2).

Hepatic and renal impairment

No dosage adjustment is required for patients with renal or mild and moderate hepatic impairment.
Limited data are available in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min). Tafamidis meglumine has not been studied in patients with severe hepatic impairment and caution is recommended (see section 5.2).

Paediatric population

There is no relevant use of tafamidis in the paediatric population.

Method of administration

Oral use.

The soft capsules should be swallowed whole and not crushed or cut. Vyndaqel may be taken with or without food.

Treatment should be initiated under the supervision of a physician knowledgeable in the management of patients with amyloidosis or cardiomyopathy.

When there is a suspicion in patients presenting with specific medical history or signs of heart failure or cardiomyopathy, etiologic diagnosis must be done by a physician knowledgeable in the management of amyloidosis or cardiomyopathy to confirm ATTR-CM and exclude AL amyloidosis before starting tafamidis, using appropriate assessment tools such as: bone scintigraphy and blood/urine assessment, and/or histological assessment by biopsy, and transthyretin (TTR) genotyping to characterise as wild-type or hereditary.

Posology

The recommended dose is one capsule of Vyndaqel 61 mg (tafamidis) orally once daily (see section 5.1).

Vyndaqel 61 mg (tafamidis) corresponds to 80 mg tafamidis meglumine. Tafamidis and tafamidis meglumine are not interchangeable on a per mg basis (see section 5.2).

Vyndaqel should be started as early as possible in the disease course when the clinical benefit on disease progression could be more evident. Conversely, when amyloid-related cardiac damage is more

advanced, such as in NYHA Class III, the decision to start or maintain treatment should be taken at the discretion of a physician knowledgeable in the management of patients with amyloidosis or cardiomyopathy (see section 5.1). There are limited clinical data in patients with NYHA Class IV.

If vomiting occurs after dosing, and the intact Vyndaqel capsule is identified, then an additional dose of Vyndaqel should be administered if possible. If no capsule is identified, then no additional dose is necessary, with resumption of dosing the next day as usual.

Special populations

Elderly

No dosage adjustment is required for elderly patients (≥ 65 years) (see section 5.2).

Hepatic and renal impairment

No dosage adjustment is required for patients with renal or mild and moderate hepatic impairment.
Limited data are available in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min). Tafamidis has not been studied in patients with severe hepatic impairment and caution is recommended (see section 5.2).

Paediatric population

There is no relevant use of tafamidis in the paediatric population.

Method of administration

Oral use.

The soft capsules should be swallowed whole and not crushed or cut. Vyndaqel may be taken with or without food.

Treatment should be initiated under the supervision of a physician knowledgeable in the management of patients with amyloidosis or cardiomyopathy.

When there is a suspicion in patients presenting with specific medical history or signs of heart failure or cardiomyopathy, etiologic diagnosis must be done by a physician knowledgeable in the management of amyloidosis or cardiomyopathy to confirm ATTR-CM and exclude AL amyloidosis before starting tafamidis, using appropriate assessment tools such as: bone scintigraphy and blood/urine assessment, and/or histological assessment by biopsy, and transthyretin (TTR) genotyping to characterise as wild-type or hereditary.

Posology

The recommended dose is one tablet of Vyndaqel 61 mg (tafamidis) orally once daily (see section 5.1).

Vyndaqel 61 mg (tafamidis) corresponds to 80 mg tafamidis meglumine. Tafamidis and tafamidis meglumine are not interchangeable on a per mg basis (see section 5.2).

No dose adjustment is required when changing from Vyndaqel 61 mg soft capsule to Vyndaqel 61 mg film-coated tablet.

Vyndaqel should be started as early as possible in the disease course when the clinical benefit on disease progression could be more evident. Conversely, when amyloid-related cardiac damage is more advanced, such as in NYHA Class III, the decision to start or maintain treatment should be taken at the discretion of a physician knowledgeable in the management of patients with amyloidosis or cardiomyopathy (see section 5.1). There are limited clinical data in patients with NYHA Class IV.

If vomiting occurs after dosing, and the intact Vyndaqel tablet is identified, then an additional dose of Vyndaqel should be administered if possible. If no tablet is identified, then no additional dose is necessary, with resumption of dosing the next day as usual.

Special populations

Elderly

No dosage adjustment is required for elderly patients (≥ 65 years) (see section 5.2).

Hepatic and renal impairment

No dosage adjustment is required for patients with renal or mild and moderate hepatic impairment.
Limited data are available in patients with severe renal impairment (creatinine clearance less than or equal to 30 mL/min). Tafamidis has not been studied in patients with severe hepatic impairment and caution is recommended (see section 5.2).

Paediatric population

There is no relevant use of tafamidis in the paediatric population.

Method of administration

Oral use.

The film-coated tablets should be swallowed whole and not crushed or cut. Vyndaqel may be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

The overall clinical data reflect exposure of 127 patients with ATTR-PN to 20 mg of tafamidis meglumine administered daily for an average of 538 days (ranging from 15 to 994 days). The adverse reactions were generally mild or moderate in severity.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA System Organ Class (SOC) and frequency categories using the standard convention: Very common ( 1/10), Common ( 1/100 to < 1/10), and Uncommon ( 1/1,000 to < 1/100). Within the frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions reported from the clinical programme in the tabular listing below reflect the rates at which they occurred in the Phase 3, double-blind, placebo-controlled study (Fx-005).

System Organ Class
Very Common
Infections and infestations
Urinary tract infection
Gastrointestinal disorders
Diarrhoea
Upper abdominal pain

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Summary of the safety profile

The safety data reflect exposure of 176 patients with ATTR-CM to 80 mg (administered as 4 x 20 mg) of tafamidis meglumine administered daily in a 30-month placebo-controlled trial in patients diagnosed with ATTR-CM (see section 5.1).

The frequency of adverse events in patients treated with 80 mg tafamidis meglumine was generally similar and comparable to placebo.

The following adverse events were reported more often in patients treated with tafamidis meglumine 80 mg compared to placebo: flatulence [8 patients (4.5%) versus 3 patients (1.7%)] and liver function test increased [6 patients (3.4%) versus 2 patients (1.1%)]. A causal relationship has not been established.

Safety data for tafamidis 61 mg are available from its open-label long-term extension study.

Tabulated list of adverse reactions

Adverse reactions are listed below by MedDRA System Organ Class (SOC) and frequency categories using the standard convention: Very common ( 1/10), Common ( 1/100 to < 1/10), and Uncommon ( 1/1,000 to < 1/100). Within the frequency group, adverse reactions are presented in order of decreasing seriousness. Adverse reactions listed in the table below are from cumulative clinical data in ATTR-CM participants.

System Organ Class
Common
Gastrointestinal disorders
Diarrhoea
Skin and subcutaneous tissue disorders
Rash
Pruritus

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Women of childbearing potential should use appropriate contraception when taking tafamidis meglumine and continue to use appropriate contraception for 1-month after stopping treatment with tafamidis meglumine (see section 4.6).

Tafamidis meglumine should be added to the standard of care for the treatment of patients with ATTR-PN. Physicians should monitor patients and continue to assess the need for other therapy, including the need for liver transplantation, as part of this standard of care. As there are no data available regarding the use of tafamidis meglumine post-liver transplantation, tafamidis meglumine should be discontinued in patients who undergo liver transplantation.

Co-administration of tafamidis meglumine with substrates of the breast cancer resistant protein (BCRP) may increase exposure to the BCRP substrate. In case of co-administration, patients should be monitored for BCRP substrate related adverse reactions, and dose reduction of the BCRP substrate may be considered (see section 4.5).

This medicinal product contains no more than 44 mg sorbitol in each capsule. Sorbitol is a source of fructose.

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

Women of childbearing potential should use appropriate contraception when taking tafamidis and continue to use appropriate contraception for 1-month after stopping treatment with tafamidis (see section 4.6).

Tafamidis should be added to the standard of care for the treatment of patients with transthyretin amyloidosis. Physicians should monitor patients and continue to assess the need for other therapy, including the need for organ transplantation, as part of this standard of care. As there are no data available regarding the use of tafamidis in organ transplantation, tafamidis should be discontinued in patients who undergo organ transplantation.

Increase in liver function tests and decrease in thyroxine may occur (see section 4.5 and 4.8).

Co-administration of tafamidis with substrates of the breast cancer resistant protein (BCRP) may increase exposure to the BCRP substrate. In case of co-administration, patients should be monitored for BCRP substrate related adverse reactions, and dose reduction of the BCRP substrate may be considered (see section 4.5).

This medicinal product contains no more than 44 mg sorbitol in each capsule. Sorbitol is a source of fructose.

The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account.

The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly.

Women of childbearing potential should use appropriate contraception when taking tafamidis and continue to use appropriate contraception for one-month after stopping treatment with tafamidis (see section 4.6).

Tafamidis should be added to the standard of care for the treatment of patients with transthyretin amyloidosis. Physicians should monitor patients and continue to assess the need for other therapy, including the need for organ transplantation, as part of this standard of care. As there are no data available regarding the use of tafamidis in organ transplantation, tafamidis should be discontinued in patients who undergo organ transplantation.

Increase in liver function tests and decrease in thyroxine may occur (see section 4.5 and 4.8).

Co-administration of tafamidis with substrates of the breast cancer resistant protein (BCRP) may increase exposure to the BCRP substrate. In case of co-administration, patients should be monitored for BCRP substrate related adverse reactions, and dose reduction of the BCRP substrate may be considered (see section 4.5).

Excipients

Lactose monohydrate

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

In a clinical study in healthy volunteers, 20 mg tafamidis meglumine did not induce or inhibit the cytochrome P450 enzyme CYP3A4.

In vitro tafamidis inhibits the efflux transporter BCRP with IC50=1.16 µM and may cause drug-drug interactions at clinically relevant concentrations with substrates of this transporter (e.g. methotrexate, rosuvastatin, atorvastatin, apixaban, rivaroxaban, imatinib). In a clinical study in healthy participants, the exposure of the BCRP substrate rosuvastatin increased approximately 2-fold following multiple

daily doses of 61 mg tafamidis. Therefore, patients should be monitored for BCRP substrate related adverse reactions when used concomitantly with tafamidis. A dose reduction of the BCRP substrate may be considered (see section 4.4).

Likewise, tafamidis inhibits the uptake transporters OAT1 and OAT3 (organic anion transporters) with IC50=2.9 µM and IC50=2.36 µM, respectively, and may cause drug-drug interactions at clinically relevant concentrations with substrates of these transporters (e.g. non-steroidal anti-inflammatory drugs, bumetanide, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, ganciclovir, adefovir, cidofovir, zidovudine, zalcitabine). Based on in vitro data, the maximal predicted changes in AUC of OAT1 and OAT3 substrates were determined to be less than 1.25 for the tafamidis meglumine 20 mg dose, therefore, inhibition of OAT1 or OAT3 transporters by tafamidis is not expected to result in clinically significant interactions.

No interaction studies have been performed evaluating the effect of other medicinal products on tafamidis meglumine.

Laboratory test abnormality

Tafamidis may decrease serum concentrations of total thyroxine, without an accompanying change in free thyroxine (T4) or thyroid stimulating hormone (TSH). This observation in total thyroxine values may likely be the result of reduced thyroxine binding to or displacement from transthyretin (TTR) due to the high binding affinity tafamidis has to the TTR thyroxine receptor. No corresponding clinical findings consistent with thyroid dysfunction have been observed.

In a clinical study in healthy volunteers, 20 mg tafamidis meglumine did not induce or inhibit the cytochrome P450 enzyme CYP3A4.

In vitro tafamidis inhibits the efflux transporter BCRP at the 61 mg/day tafamidis dose with IC50=1.16 µM and may cause drug-drug interactions at clinically relevant concentrations with substrates of this transporter (e.g. methotrexate, rosuvastatin, atorvastatin, apixaban, rivaroxaban, imatinib). In a clinical study in healthy participants, the exposure of the BCRP substrate rosuvastatin increased approximately 2-fold following multiple daily doses of 61 mg tafamidis. Therefore, patients should be monitored for BCRP substrate related adverse reactions when used concomitantly with tafamidis. A dose reduction of the BCRP substrate may be considered (see section 4.4).

Likewise, tafamidis inhibits the uptake transporters OAT1 and OAT3 (organic anion transporters) with IC50=2.9 µM and IC50=2.36 µM, respectively, and may cause drug-drug interactions at clinically relevant concentrations with substrates of these transporters (e.g. non-steroidal anti-inflammatory drugs, bumetanide, furosemide, lamivudine, methotrexate, oseltamivir, tenofovir, ganciclovir, adefovir, cidofovir, zidovudine, zalcitabine). Based on in vitro data, the maximal predicted changes in AUC of OAT1 and OAT3 substrates were determined to be less than 1.25 for the tafamidis 61 mg dose, therefore, inhibition of OAT1 or OAT3 transporters by tafamidis is not expected to result in clinically significant interactions.

No interaction studies have been performed evaluating the effect of other medicinal products on tafamidis.

Laboratory test abnormality

Tafamidis may decrease serum concentrations of total thyroxine, without an accompanying change in free thyroxine (T4) or thyroid stimulating hormone (TSH). This observation in total thyroxine values may likely be the result of reduced thyroxine binding to or displacement from TTR due to the high binding affinity tafamidis has to the TTR thyroxine receptor. No corresponding clinical findings consistent with thyroid dysfunction have been observed.

Women of childbearing potential

Contraceptive measures should be used by women of childbearing potential during treatment with tafamidis meglumine, and for one month after stopping treatment, due to the prolonged half-life.

Pregnancy

There are no data on the use of tafamidis meglumine in pregnant women. Studies in animals have shown developmental toxicity (see section 5.3). Tafamidis meglumine is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Available data in animals have shown excretion of tafamidis in milk. A risk to the newborns/infants cannot be excluded. Tafamidis meglumine should not be used during breast-feeding.

Fertility

No impairment of fertility has been observed in nonclinical studies (see section 5.3).

Women of childbearing potential

Contraceptive measures should be used by women of childbearing potential during treatment with tafamidis, and for one month after stopping treatment, due to the prolonged half-life.

Pregnancy

There are no data on the use of tafamidis in pregnant women. Studies in animals have shown developmental toxicity (see section 5.3). Tafamidis is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

Available data in animals have shown excretion of tafamidis in milk. A risk to the newborns/infants cannot be excluded. Tafamidis should not be used during breast-feeding.

Fertility

No impairment of fertility has been observed in nonclinical studies (see section 5.3).

On the basis of the pharmacodynamic and pharmacokinetic profile, tafamidis meglumine is believed to have no or negligible influence on the ability to drive or use machines.

On the basis of the pharmacodynamic and pharmacokinetic profile, tafamidis is believed to have no or negligible influence on the ability to drive or use machines.

Symptoms

There is minimal clinical experience with overdose. During clinical trials, two patients diagnosed with transthyretin amyloid cardiomyopathy (ATTR-CM) accidentally ingested a single tafamidis meglumine dose of 160 mg without the occurrence of any associated adverse events. The highest dose of tafamidis meglumine given to healthy volunteers in a clinical trial was 480 mg as a single dose.
There was one reported treatment-related adverse event of mild hordeolum at this dose.

Management

In case of overdose, standard supportive measures should be instituted as required.

5.
PHARMACOLOGIC PROPERTIES

Symptoms

There is minimal clinical experience with overdose. During clinical trials, two patients diagnosed with ATTR-CM accidentally ingested a single tafamidis meglumine dose of 160 mg without the occurrence of any associated adverse events. The highest dose of tafamidis meglumine given to healthy volunteers in a clinical trial was 480 mg as a single dose. There was one reported treatment-related adverse event of mild hordeolum at this dose.

Management

In case of overdose, standard supportive measures should be instituted as required.

5.
PHARMACOLOGIC PROPERTIES

Pharmacotherapeutic group: Other nervous system drugs, ATC code N07XX08

Mechanism of action

Tafamidis is a selective stabiliser of TTR. Tafamidis binds to TTR at the thyroxine binding sites, stabilising the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process.

Pharmacodynamic effects

Transthyretin amyloidosis is a severely debilitating condition induced by the accumulation of various insoluble fibrillar proteins, or amyloid, within the tissues in amounts sufficient to impair normal function. The dissociation of the transthyretin tetramer to monomers is the rate-limiting step in the pathogenesis of transthyretin amyloidosis. The folded monomers undergo partial denaturation to produce alternatively folded monomeric amyloidogenic intermediates. These intermediates then misassemble into soluble oligomers, profilaments, filaments, and amyloid fibrils. Tafamidis binds with negative cooperativity to the two thyroxine binding sites on the native tetrameric form of transthyretin preventing dissociation into monomers. The inhibition of TTR tetramer dissociation forms the rationale for the use of tafamidis to slow disease progression in stage 1 ATTR-PN patients.

A TTR stabilisation assay was utilised as a pharmacodynamic marker and assessed the stability of the TTR tetramer.

Tafamidis stabilised both the wild-type TTR tetramer and the tetramers of 14 TTR variants tested clinically after once-daily dosing with tafamidis. Tafamidis also stabilised the TTR tetramer for 25 variants tested ex vivo, thus demonstrating TTR stabilisation of 40 amyloidogenic TTR genotypes.

Clinical efficacy and safety

The pivotal study of tafamidis meglumine in stage 1 ATTR-PN patients was an 18-month, multicentre, randomised, double-blind, placebo-controlled study. The study evaluated the safety and efficacy of once-daily 20 mg tafamidis meglumine in 128 patients with ATTR-PN with the Val30Met mutation and primarily stage 1 disease; 126 of the 128 patients did not routinely require assistance with ambulation. The primary outcome measures were the Neuropathy Impairment Score of the Lower Limb (NIS-LL – a physician assessment of the neurologic exam of the lower limbs) and the Norfolk Quality of Life - Diabetic Neuropathy (Norfolk QOL-DN – a patient reported outcome, total quality of life score [TQOL]). Other outcome measures included composite scores of large nerve fibre (nerve conduction, vibration threshold and heart rate response to deep breathing - HRDB) and small nerve fibre function (heat pain and cooling threshold and HRDB) and nutritional assessments utilizing the modified body mass index (mBMI – BMI multiplied by serum albumin in g/L). Eighty-six of the 91 patients completing the 18 month treatment period subsequently enrolled in an open-label extension study, where they all received once daily 20 mg tafamidis meglumine for an additional 12 months.

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX08

Mechanism of action

Tafamidis is a selective stabiliser of TTR. Tafamidis binds to TTR at the thyroxine binding sites, stabilising the tetramer and slowing dissociation into monomers, the rate-limiting step in the amyloidogenic process.

Pharmacodynamic effects

Transthyretin amyloidosis is a severely debilitating condition induced by the accumulation of various insoluble fibrillar proteins, or amyloid, within the tissues in amounts sufficient to impair normal function. The dissociation of the transthyretin tetramer to monomers is the rate-limiting step in the pathogenesis of transthyretin amyloidosis. The folded monomers undergo partial denaturation to produce alternatively folded monomeric amyloidogenic intermediates. These intermediates then misassemble into soluble oligomers, profilaments, filaments, and amyloid fibrils. Tafamidis binds with negative cooperativity to the two thyroxine binding sites on the native tetrameric form of transthyretin preventing dissociation into monomers. The inhibition of TTR tetramer dissociation forms the rationale for the use of tafamidis in ATTR-CM patients.

A TTR stabilisation assay was utilised as a pharmacodynamic marker, and assessed the stability of the TTR tetramer.

Tafamidis stabilised both the wild-type TTR tetramer and the tetramers of 14 TTR variants tested clinically after once-daily dosing with tafamidis. Tafamidis also stabilised the TTR tetramer for 25 variants tested ex vivo, thus demonstrating TTR stabilisation of 40 amyloidogenic TTR genotypes.

In a multicentre, international, double-blind, placebo-controlled, randomised study (see Clinical efficacy and safety section), TTR stabilisation was observed at Month 1 and was maintained through Month 30.

Biomarkers associated with heart failure (NT-proBNP and Troponin I) favoured Vyndaqel over placebo.

Clinical efficacy and safety

Efficacy was demonstrated in a multicentre, international, double-blind, placebo-controlled, randomised 3-arm study in 441 patients with wild-type or hereditary ATTR-CM.

Patients were randomised to either tafamidis meglumine 20 mg (n=88) or 80 mg [administered as four 20 mg tafamidis meglumine capsules] (n=176) or matching placebo (n=177) once daily, in addition to standard of care (e.g. diuretics) for 30 months. Treatment assignment was stratified by the presence or absence of a variant TTR genotype as well as by baseline severity of disease (NYHA Class). Table 1 describes the patient demographics and baseline characteristics.

Table 1: Patient demographics and baseline characteristics

Characteristic
Pooled Tafamidis
N=264
Placebo
N=177
Age — year
Mean (standard deviation)

Absorption

After oral administration of the soft capsule once daily, the maximum peak concentration (Cmax) is achieved within a median time (tmax) of 4 hours after dosing in the fasted state. Concomitant administration of a high fat, high calorie meal altered the rate of absorption, but not the extent of absorption. These results support the administration of tafamidis with or without food.

Distribution

Tafamidis is highly protein bound (> 99%) in plasma. The apparent steady-state volume of distribution is 16 litres.

The extent of tafamidis binding to plasma proteins has been evaluated using animal and human plasma. The affinity of tafamidis for TTR is greater than that for albumin. Therefore, in plasma, tafamidis is likely to bind preferentially to TTR despite the significantly higher concentration of albumin (600 μM) relative to TTR (3.6 μM).

Biotransformation and elimination

There is no explicit evidence of biliary excretion of tafamidis in humans. Based on preclinical data, it is suggested that tafamidis is metabolised by glucuronidation and excreted via the bile. This route of biotransformation is plausible in humans, as approximately 59% of the total administered dose is recovered in faeces, and approximately 22% recovered in urine. Based on population pharmacokinetic results, the apparent oral clearance of tafamidis meglumine is 0.228 L/h and the population mean half-life is approximately 49 hours.

Dose and time linearity

Exposure from once-daily dosing with tafamidis meglumine increased with increasing dose up to 480 mg single dose and multiple doses up to 80 mg/day. In general, increases were proportional or near proportional to dose and tafamidis clearance was stationary over time.

Pharmacokinetic parameters were similar after single and repeated administration of 20 mg tafamidis meglumine, indicating a lack of induction or inhibition of tafamidis metabolism.

Absorption

After oral administration of the soft capsule once daily, the maximum peak concentration (Cmax) is achieved within a median time (tmax) of 4 hours for tafamidis 61 mg and 2 hours for tafamidis meglumine 80 mg (4 x 20 mg) after dosing in the fasted state. Concomitant administration of a high fat, high calorie meal altered the rate of absorption, but not the extent of absorption. These results support the administration of tafamidis with or without food.

Distribution

Tafamidis is highly protein bound (> 99%) in plasma. The apparent steady-state volume of distribution is 18.5 litres.

The extent of tafamidis binding to plasma proteins has been evaluated using animal and human plasma. The affinity of tafamidis for TTR is greater than that for albumin. Therefore, in plasma, tafamidis is likely to bind preferentially to TTR despite the significantly higher concentration of albumin (600 μM) relative to TTR (3.6 μM).

Biotransformation and elimination

There is no explicit evidence of biliary excretion of tafamidis in humans. Based on preclinical data, it is suggested that tafamidis is metabolised by glucuronidation and excreted via the bile. This route of biotransformation is plausible in humans, as approximately 59% of the total administered dose is recovered in faeces, and approximately 22% recovered in urine. Based on population pharmacokinetic results, the apparent oral clearance of tafamidis is 0.263 L/h and the population mean half-life is approximately 49 hours.

Dose and time linearity

Exposure from once-daily dosing with tafamidis meglumine increased with increasing dose up to 480 mg single dose and multiple doses up to 80 mg/day. In general, increases were proportional or near proportional to dose and tafamidis clearance was stationary over time.

The relative bioavailability of tafamidis 61 mg is similar to tafamidis meglumine 80 mg at steady-state. Tafamidis and tafamidis meglumine are not interchangeable on a per mg basis.

Absorption

After oral administration of the film-coated tablet once daily, the maximum peak concentration (Cmax) is achieved within a median time (tmax) of 4 hours for tafamidis 61 mg after dosing in the fasted state.
Concomitant administration of a high fat, high calorie meal altered the rate of absorption, but not the extent of absorption. These results support the administration of tafamidis with or without food.

Distribution

Tafamidis is highly protein bound (> 99%) in plasma. The apparent steady-state volume of distribution is 18.5 litres.

The extent of tafamidis binding to plasma proteins has been evaluated using animal and human plasma. The affinity of tafamidis for TTR is greater than that for albumin. Therefore, in plasma, tafamidis is likely to bind preferentially to TTR despite the significantly higher concentration of albumin (600 μM) relative to TTR (3.6 μM).

Biotransformation and elimination

There is no explicit evidence of biliary excretion of tafamidis in humans. Based on preclinical data, it is suggested that tafamidis is metabolised by glucuronidation and excreted via the bile. This route of biotransformation is plausible in humans, as approximately 59% of the total administered dose is recovered in faeces, and approximately 22% recovered in urine. Based on population pharmacokinetic results, the apparent oral clearance of tafamidis is 0.263 L/h and the population mean half-life is approximately 49 hours.

Dose and time linearity

Exposure from once-daily dosing with tafamidis meglumine increased with increasing dose up to 480 mg single dose and multiple doses up to 80 mg/day. In general, increases were proportional or near proportional to dose and tafamidis clearance was stationary over time.

The relative bioavailability of tafamidis 61 mg is similar to tafamidis meglumine 80 mg at steady-state. Tafamidis and tafamidis meglumine are not interchangeable on a per mg basis.