Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

14.2 Pharmacodynamics
Cardiac Electrophysiology
The largest mean increase in QTc was 24 msec (UCI: 31 msec) following administration of levoketoconazole 150 mg to 600 mg twice daily (the approved recommended dosage) in patie ts ith e doge ous Cushi g’s s dro e. The i rease i QT as dose-related.

Pharmacokinetic Properties

14.3 Pharmacokinetics
Absorption
Peak plasma concentrations of levoketoconazole occur approximately 1.5 to 2 hours following oral administration of a single dose of RECORLEV under fasted conditions regardless of dose. In healthy volunteers, Cmax increases approximately proportionally with dose, while AUC increases greater than dose proportionally from 150 mg to 600 mg.
Levoketoconazole accumulates in plasma during multiple dosing of RECORLEV.
Levoketoconazole is a substrate of the intestinal (and liver) efflux transporter, P-gp.
Effect of Food
In a healthy volunteer study (N = 24), subjects administered a single, 600 mg oral dose of RECORLEV tablets with a high-fat meal (total caloric content of 875 calories; 160 protein calories, 170 carbohydrate calories, and 545 fat calories) resulted in an increase of AUC by 30% and no change in Cmax. The median Tmax was delayed from 2 to 4 hours. These changes are not considered to be clinically significant.
Distribution
Levoketoconazole has an apparent volume of distribution of 31 to 41 L, approximating total body water. Protein binding of levoketoconazole in human plasma is high (99.3%).
Elimination
Metabolism
No in vitro or in vivo studies of levoketoconazole metabolism have been performed. Racemic ketoconazole is metabolized extensively in the liver to several inactive metabolites (with respect to antifungal activity). CYP3A4 is the major enzyme involved in the metabolism of ketoconazole. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings. In addition, oxidative O- dealkylation and aromatic hydroxylation occurs.
Excretion
Levoketoconazole is eliminated from plasma with a half-life of 3 to 4.5 hours after a single dose and 4 to 6 hours after multiple doses.
A mass-balance study has not been performed with levoketoconazole. Approximately 13% of a racemic ketoconazole dose is excreted in the urine, of which 2 to 4% is unchanged drug.
The major route of excretion is through the bile into the intestinal tract with about 57% being excreted in the feces.
Specific Populations
Populatio phar a oki eti odeli g data fro patie ts ith Cushi g’s s dro e suggest there is no impact of age or sex on the pharmacokinetics of levoketoconazole. The pharmacokinetics of levoketoconazole have not been formally studied in geriatric patients.
Levoketoconazole has not been studied in patients younger than 18 years of age. Differences in pharmacokinetics among race/ethnicity groups are unknown.
Patients with Renal or Hepatic Impairment
Levoketoconazole has not been studied in patients with renal or hepatic impairment. The overall pharmacokinetics of racemic ketoconazole was not significantly altered in patients with renal failure when compared with healthy volunteers. [see Contraindications (7)]. Given the extensive hepatic metabolism of ketoconazole, it is expected that clearance would be reduced in patients with impaired liver function.
Drug Interaction Studies
Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. Concomitant administration of medications that are substrates of these enzymes or transporters may have their plasma concentrations affected by RECORLEV [see Drug Interactions (10.1)].
Clinical drug interaction studies were conducted to evaluate the effects of levoketoconazole on the pharmacokinetics of atorvastatin, felodipine, and metformin in healthy volunteers.
Results are displayed in Table 8. For clinical recommendations regarding these interactions, [see Drug Interactions (10.1)].

Table 8: Change in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Levoketoconazole
Ratio of Least Square Means (90%
Coadministered Drug        N       Levoketoconazole Dose           Confidence Interval) a AUC0-∞               Cmax
317.6%               96.7%
Atorvastatin                 23     400 mg once daily
(286.6-352.0%)      (82.3 – 113.6%)

1007.3%             937.1%
Felodipine                   14     400 mg once daily
(868.8-1167.9%)     (757.9-1158.8%)

220%                   182%
Metformin                    17     450 mg twice daily
(203 –239%)            (168 – 197%) a
For coadministered drug + levoketoconazole vs coadministered drug alone.
In Vitro Studies Where Drug Interaction Potential was not Further Evaluated Clinically In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8, and induces CYP1A2.
Levoketoconazole does not inhibit CYP1A2, CYP2C9, CYP2C19, or CYP2D6, does not induce CYP2B6, and does not inhibit the OATP1B3, OAT1, OAT3, or MATE2-K transporters.