Olanzapine pharmacokinetics

There is little published information that directly examines ethnic differences in olanzapine pharmacokinetics or pharmacodynamics. Indirectly, examining stable... 

Grothe, D.R., Calis, K.A., Jacobsen, L., Kumra, S., DeVane, C.L., Rapoport, J.L., Bergstrom, R.F., and Kurtz, D.L. (2000) Olanzapine pharmacokinetics in pediatric and adolescent inpatients with childhood-onset schizophrenia. 1 Clin Psychopharmacol 20 220-225. 

Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine. Pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999 37(3) 177-93. 

A study in 43 healthy subjects found that steady-state olanzapine pharmacokinetics were not affected by lamotiigine 200 mg daily. However, the AUC and maximum plasma concentrations of lamotiigine were reduced by 24% and 20%, respectively. Although this reduction was not considered to be clinically significant, interpatient variation indicated that some patients may require adjustment of their lamotiigine dose if olanzapine is started or discontinued. ... 

Penzak SR, Hon YY, Lawhom WD, Shirley KL, Sirratlin V, Jarm MW. Influence of ritonavir on olanzapine pharmacokinetics in healthy volunteers. J Clin Psychopharmacol (2002) 22,... 

Wrighton SA, Ring BJ. Predicting drug interactions and pharmacokinetic variability with in vitro methods the olanzapine experience. Drug Metab Rev 1999 31 15-28. 

TABLE 5-27. Pharmacokinetics of risperidone, olanzapine, quetiapine, and ziprasidone... 

Pharmacokinetic and pharmacodynamic profiles of olanzapine have been extensively reviewed (114). Olanzapine does not inhibit CYP isozymes, and no clinically significant metabolic interaction was found with fluoxetine. 

Fluvoxamine increases clozapine plasma concentrations (SEDA-27, 58). and the differential effects of steady-state fluvoxamine on the pharmacokinetics of olanzapine and clozapine have been studied in healthy volunteers (256). Fluvoxamine significantly reduced the N-des-methylclozapine to clozapine ratio, implying reduced metabolism of clozapine. 

Lucas RA, Gilfillan DJ, Bergstrom RF. A pharmacokinetic interaction between carbamazepine and olanzapine observations on possible mechanism. Eur J Clin Pharmacol 1998 54(8) 639-43. 

In healthy subjects, olanzapine did not affect theophylline pharmacokinetics (70). These results confirm the earlier reported in vitro findings that olanzapine is not a potent inhibitor of CYP1A2 (71). 

Macias WL, Bergstrom RE, Cerimele BJ, Kassahun K, Tatum DE, Callaghan JT. Lack of effect of olanzapine on the pharmacokinetics of a single aminophylline dose in healthy men. Pharmacotherapy 1998 18(6) 1237 8. 

The biotransformation (468-470)and clinical pharmacokinetics (471) of olanzapine have been investigated extensively. The drug exhibits dose proportional linear pharmacokinetics in therapeutic dose ranges (471). Olanzapine is bound to both albumin and a-l-acid glycoproteins in the plasma. The mean elimination half-life in healthy adults was 33 h and the plasma clearance averaged 26 L/h. 

Loose binding to striatal D2-like receptors clozapine, quetiapine, risperidone, sertindole, olanzapine (but may be a pharmacokinetic rather than pharmacodynamic effect). 

Thus, valproate is often used to reduce the risk for clozapine-induced seizures. Carbamazepine can potentially increase the risk for development of agranulocytosis when coadministered with clozapine, so this combination should be avoided. Carbamazepine increases renal clearance of olanzapine by about 45% and reduces its half-life by about 20%. To date, no pharmacokinetic interactions have been reported between aripiprazole and valproate. 

Antidepressants Fluvoxamlne, a potent inhibitor of the cytochrome P450 enzymes CYP1A2 and CYP2C19 and a moderate inhibitor of CYP3A4, has been reported to cause a 5-10-fold elevation of plasma clozapine concentration. Fluoxetine and paroxetine may also increase plasma clozapine concentrations, while citalopram and sertraline have been reported to cause minimal or no elevation of plasma levels of clozapine. To date, in vivo studies with a combined olanzapine-imipramine regimen have not revealed any pharmacokinetic interactions. 

The combined regimen is safe and effective, although severe cardiovascular or respiratory adverse effects may occur with high doses of clozapine when combined with diazepam and lorazepam. There are no reports of pharmacokinetic interactions between olanzapine and benzodiazepines (studied mainly with diazepam). 

---