KYNMOBI (Page 5 of 7)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

KYNMOBI is a non-ergoline dopamine agonist with high in vitro binding affinity for the dopamine D4 receptor, and moderate affinity for the dopamine D2 , D3 , and D5 , and adrenergic α1 D, α2 B, α2 C receptors. The precise mechanism of action of KYNMOBI as a treatment for “off” episodes associated with Parkinson’s disease is unknown, although it is believed to be due to stimulation of post-synaptic dopamine D2 -type receptors within the caudate-putamen in the brain.

12.2 Pharmacodynamics

Cardiac Electrophysiology

In a thorough QT study with subcutaneous apomorphine at exposures similar to those achieved with the recommended subcutaneous apomorphine dosing (i.e, 6 mg), apomorphine resulted in a prolongation of QTcF of 10 msec (90% upper confidence interval of 16 msec). The thorough QT study also identified a significant exposure-response relationship between apomorphine concentration and QTcF.

Although the extent of the exposure and the Cmax of apomorphine are lower following the maximum recommended dose of KYNMOBI (30 mg) than following the maximum recommend dose of subcutaneous apomorphine (6 mg), QTc prolongation with KYNMOBI cannot be excluded.

Decreases in Blood Pressure

In Study 1, systolic orthostatic hypotension (reduction of 20 mmHg or more in standing minus supine/sitting systolic blood pressure) or diastolic hypotension (10 mmHg or more for standing minus supine/sitting diastolic blood pressure) occurred in 43% of patients treated with KYNMOBI, compared to 36% of patients who received placebo [see Warnings and Precautions (5.4) and Drug Interactions (7.2, 7.3)].

12.3 Pharmacokinetics

Absorption

Following sublingual administration of 15 mg of apomorphine, the time to maximum concentration (Tmax ) ranged from 0.5 to 1 hour. Apomorphine exhibits less than dose-proportional increase in exposures over a dose range of 10 mg to 35 mg (1.2 times the highest recommended dosage) following a single sublingual administration of KYNMOBI in patients with Parkinson’s disease.

Distribution

Following sublingual administration of 15 mg of apomorphine, the geometric mean (CV%) of the apparent volume of distribution was 3630 L (66%).

Elimination

Metabolism

The major metabolic pathways for sublingual apomorphine are sulfation by multiple sulfotransferase (SULT) enzymes; glucuronidation by multiple glycosyltransferase (UGT) enzymes; N-demethylation catalyzed by multiple enzymes, including CYP2B6, CYP2C8, and CYP3A4/5; followed by conjugation. Metabolism of sublingual apomorphine results in 3 major inactive metabolites: apomorphine sulfate, apomorphine glucuronide, and norapomorphine glucuronide.

Excretion

Following sublingual administration of 15 mg of apomorphine, the geometric mean (CV%) of the apparent clearance was 1440 L/h (68%), and the geometric mean of the terminal elimination half-life is about 1.7 hours (range about 0.8 hour to 3 hours).

Specific Populations

The apparent clearance of apomorphine does not appear to be influenced by age, gender, race, weight, duration of Parkinson’s disease, levodopa dose, use of antiemetic, or duration of therapy.

Renal Impairment

The clinical studies of KYNMOBI included patients with mild renal impairment (CLcr of ≥60 mL/min and <90 mL/min). There were no differences in apomorphine exposure after administration of KYNMOBI in patients with mild renal impairment as compared to patients with normal renal function (CLcr of ≥90 mL/min). Studies with KYNMOBI in patients with moderate to severe renal impairment have not been conducted.

In a study with subcutaneous apomorphine comparing patients with moderate renal impairment (as determined by estimated creatinine clearance) to healthy matched volunteers, the AUC0- and Cmax values were increased by approximately 16% and 50%, respectively, following a single administration. The mean time to peak concentrations and the mean terminal half-life of apomorphine were unaffected by the renal status of the individual.

Since the Cmax and AUC0- of apomorphine following the sublingual administration are lower as compared to the subcutaneous route of administration and the KYNMOBI dose is titrated individually, these changes are not expected to be clinically significant for patients with mild or moderate renal impairment [see Use in Specific Populations (8.6)].

Hepatic Impairment

Studies with KYNMOBI in patients with hepatic impairment have not been conducted.

In a study with subcutaneous apomorphine comparing patients with moderate hepatic impairment (as determined by the Child-Pugh classification method) to healthy matched volunteers, the AUC0- and Cmax values were increased by approximately 10% and 25%, respectively, following a single administration. These changes are not expected to be clinically significant for patients with mild or moderate hepatic impairment [see Use in Specific Populations (8.7)].

Drug Interaction Studies

Carbidopa/levodopa

Levodopa pharmacokinetics were unchanged when subcutaneous apomorphine and levodopa were co-administrated in patients. However, motor response differences were significant. The threshold levodopa concentration necessary for an improved motor response was reduced significantly, leading to an increased duration of effect without a change in the maximal response to levodopa therapy.

Nitroglycerin

Co-administration of nitroglycerin (0.4 mg) with subcutaneous apomorphine in healthy subjects did not have a significant impact on the pharmacokinetics of apomorphine. However, concomitant administration of nitroglycerin (0.4 mg) with subcutaneous apomorphine caused greater decreases in blood pressure than with subcutaneous apomorphine alone [see Warnings and Precautions (5.4) and Drug Interactions (7.2)].

When nitroglycerin and subcutaneous apomorphine were concomitantly administered to healthy subjects, the mean largest decrease (the mean of each subject’s largest drop in blood pressure measured within the 6-hour period following administration of subcutaneous apomorphine) in supine systolic and diastolic blood pressure (measured over 6 hours) was 9.7 mm Hg and 9.3 mm Hg, respectively. The mean largest decrease in standing systolic and diastolic blood pressure was 14.3 mm Hg and 13.5 mm Hg, respectively. Some individuals experienced very large decreases in standing systolic and diastolic blood pressure, up to a maximum decrease of 65 mm Hg and 43 mm Hg, respectively. In comparison, the mean largest decrease in supine systolic and diastolic blood pressure when subcutaneous apomorphine was administered alone was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing systolic and diastolic blood pressure was 6.7 mm Hg and 8.4 mm Hg, respectively.

A similar study has not been performed with KYNMOBI.

Ethanol

Co-administration of low-dose ethanol (0.3 g/kg) with subcutaneous apomorphine in healthy subjects did not have a significant impact on the pharmacokinetics of apomorphine, but high-dose ethanol (0.6 g/kg), equivalent to approximately 3 standardized alcohol-containing beverages, increased the Cmax of apomorphine by about 63%.

When high-dose ethanol (0.6 g/kg) and subcutaneous apomorphine were concomitantly administered to healthy subjects, the mean largest decrease (the mean of each subject’s largest drop in blood pressure measured within the 6-hour period following administration of subcutaneous apomorphine) for supine systolic and diastolic blood pressure was 9.1 mm Hg and 10.5 mm Hg, respectively. The mean largest standing systolic and diastolic blood pressure decrease was 11.3 mm Hg and 12.6 mm Hg, respectively. In some individuals, the decrease was as high as 61 mm Hg and 51 mm Hg, respectively, for standing systolic and diastolic blood pressure.

When low-dose ethanol (0.3 g/kg) and subcutaneous apomorphine were concomitantly administered, the mean largest decrease in supine systolic and diastolic blood pressure was 10.2 mm Hg and 9.9 mm Hg, respectively. The mean largest decrease in standing systolic and diastolic blood pressure was 8.4 mm Hg and 7.1 mm Hg, respectively. In comparison, the mean largest decrease in supine systolic and diastolic blood pressure when subcutaneous apomorphine was administered alone was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing systolic and diastolic blood pressure was 6.7 mm Hg 8.4 mm Hg, respectively.

A similar study has not been performed with KYNMOBI.

COMT Interactions

A pharmacokinetic interaction of apomorphine with catechol-O-methyl transferase (COMT) inhibitors or drugs metabolized by this route is unlikely since apomorphine appears not to be metabolized by COMT.

In vitro studies

Based on in vitro studies, the potential for KYNMOBI to interact with concomitant medications to cause a CYP metabolism or transporter-based drug-drug interaction is considered low.

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