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RUZURGI(amifampridine)tablets(七)
ZURGI administered to healthy volunteers was recovered in urine aseither the parent compound or the 3-N-acetyl amifampridine metabolite.
Specific PopulationsPediatric Patients (6 to Less than 17 Years of Age)A population pharmacokinetic analysis showed that body weight significantly correlates with the clearance of amifampridine; clearance increased with an increase in body weight. A weight-baseddosing regimen is necessary to achieve amifampridine exposures in pediatric patients 6 to lessthan 17 years of age similar to those observed in adults at effective doses of RUZURGI [seeIndications and Usage (1) and Clinical Studies (14)].
Drug Interaction Studies
In vitro studies
Amifampridine is not metabolized by cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6,CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.
In vitro studies with human liver microsomes indicated that amifampridine and 3-N-acetylamifampridine were not direct or time-dependent inhibitors of CYP1A2, CYP2A6, CYP2B6,CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.
In vitro studies in cryopreserved human hepatocytes indicated that amifampridine did not induceCYP isoforms CYP1A2, CYP2B6, or CYP3A4.
Based on in vitro studies with Caco-2 cells amifampridine is unlikely to act as a substrate orinhibitor of the P glycoprotein transporter. Amifampridine is not an inhibitor of the BCRPtransporter.
In vitro studies with Chinese hamster ovary cells expressing human OATP1B1, OATP1B3,OAT1, and OCT2 and Madin-Darby canine kidney cells expressing human OAT3 indicated thatamifampridine is a weak inhibitor of OCT2, but is not an inhibitor of OAT1, OAT3, OATP1B1,or OATP1B3. The studies also indicated that amifampridine is not a substrate for OAT1, OAT3,or OCT2 transporters.
In vivo studies
Controlled clinical drug interaction studies have not been performed with RUZURGI.
Co-administration of intravenous amifampridine and intravenous pyridostigmine led to a 21%elevation in maximum pyridostigmine serum concentrations, but did not significantly affect thepharmacokinetics of amifampridine [see Drug Interactions (7.2)].
12.5 Pharmacogenomics
Genetic variants in the N-acetyltransferase gene 2 (NAT2) affect the rate and extent ofRUZURGI metabolism. In normal healthy volunteers, poor metabolizers, also referred to as“slow acetylators” (i.e., carriers of two reduced function alleles) had higher average plasmaamifampridine concentrations than intermediate metabolizers, also referred to as “intermediateacetylators” (i.e., carriers of one reduced and one normal function alleles), and normalmetabolizers, also referred to as “fast/rapid acetylators” (i.e., carriers of two normal functionalleles).
In the TQT study [see Clinical Pharmacology (12.2)], poor metabolizers (N=19) had 1.1 to 3.7times higher AUC0-4h and 1.3 to 3.7 times higher Cmax than intermediate metabolizers (N=21),following the first dose. Poor metabolizers had 6.0 to 8.5 times higher AUC0-4h and 6.1 to 7.6times higher Cmax than normal metabolizers (N=3), following the first dose.
In the general population, the NAT2 poor metabolizer phenotype preva lence is 40–60% in theWhite and African American populations, and in 10–30% in Asian ethnic populations(individuals of Japanese, Chinese, or Korean descent).
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenesis
Carcinogenicity |
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