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ADASUVE 9.1mg inhalation powder, pre-dispensed(八)
oxide, and de-methylation to form amoxapine. For ADASUVE, the order of metabolites observed in humans (based on systemic exposure) was 8-OH-loxapine >> loxapine N oxide > 7-OH-loxapine > amoxapine, with plasma levels of 8-OH-loxapine similar to the parent compound. 8-OH-loxapine is not pharmacologically active at the D2 receptor while the minor metabolite, 7-OH-loxapine, has high binding affinity to D2 receptors.
Loxapine is a substrate for several CYP450 isozymes; in vitro studies demonstrated that 7-OH-loxapine is formed mainly by CYPs 3A4 and 2D6, 8-OH-loxapine is formed mainly by CYP1A2, amoxapine is formed mainly by CYP3A4, 2C19, and 2C8, and loxapine N-oxide is formed by FMOs.
The potential for loxapine and its metabolites (amoxapine, 7-OH-loxapine, 8-OH-loxapine, and loxapine-N-oxide) to inhibit CYP450 - mediated drug metabolism has been examined in vitro for CYPs 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. No significant inhibition was observed. In vitro studies indicate that loxapine and 8-OH-loxapine are not inducers of CYP1A2, 2B6 or 3A4 enzymes at clinically relevant concentrations. In addition, in vitro studies indicate that loxapine and 8-OH loxapine are not inhibitors of UGT1A1, 1A3, 1A4, 2B7 and 2B15.
Elimination
Loxapine excretion occurs mainly in the first 24 hours. Metabolites are excreted in the urine in the form of conjugates and in the faeces unconjugated. The terminal elimination half-life (T½) ranged from 6 to 8 hours.
Linearity/non-linearity
The mean plasma loxapine concentrations following administration of ADASUVE were linear over the clinical dose range. AUC0-2h, AUCinf, and Cmax increased in a dose-dependent manner.
Pharmacokinetics in special patient populations
Smokers
A population pharmacokinetic analysis that compared exposures in smokers versus non-smokers indicated that smoking, which induces CYP1A2, had a minimal effect on the exposure to ADASUVE. No dosage adjustment is recommended based on smoking status.
In female smokers exposure (AUCinf) to ADASUVE and its active metabolite 7-OH-loxapine is lower than in female non-smokers (84% vs 109% 7-OH-loxapine/Loxapine Ratio), which is probably due to an increase in loxapine clearance in smokers.
Demographics
There were no important differences in the exposure or disposition of loxapine following administration of ADASUVE due to age, gender, race, weight, or body mass index (BMI).
5.3 Preclinical safety data
Non-clinical safety data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, and genotoxicity, except for changes to reproductive tissues related to the extended pharmacology of loxapine. Similar changes, e.g., gynecomastia, are known in humans, but only after long-term administration of medicines causing hyperprolactinaemia.
Female rats did not mate due to persistent diestrus after oral treatment with loxapine. Embryo/fetal developmental and perinatal studies have shown indications of developmental delay (reduced weights, delayed ossification, hydronephrosis, hydrourether, and/or distended renal pelvis with reduced or absent papillae) as well as increased numbers of perinatal and neonatal deaths in offspring of rats treated from mid-pregnancy with oral doses below the maximum recommended human dose for ADASUVE on a mg/m2 basis (see section 4.6).
6. Pharmaceutical particulars
6.1 List of excipients
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