Nefazodone pharmacokinetics

Findling, R.L., Preskorn, S.H., Marcus, R.N., Magnus, R.D., D Amico, R, Marathe P. and Reed, M.D., (2000) Nefazodone pharmacokinetics in depressed children and adolescents. / Am Acad Child Adolesc Psychiatry 39 1008-1016. 

Pharmacokinetic parameters of the newer antidepressants are shown in Table 35— 5.9,29 Several antidepressants are not very highly protein bound, and the most notable of these is venlafaxine. The elimination half-lives of nefazodone and... 

In our laboratories, a cycle time of 90 sec can be achieved with a dilution factor of 1 25 for a given sample concentration, allowing the purity and identity control of two and a half 384-well microtiter plates per day. The online dilution eliminated an external step in the workflow and reduced the risks of decomposition of samples in the solvent mixture (weakly acidic aqueous solvent) required for analysis. Mao et al.23 described an example in which parallel sample preparation reduced steps in the workflow. They described a 2-min cycle time for the analysis of nefazodone and its metabolites for pharmacokinetic studies. The cycle time included complete solid phase extraction of neat samples, chromatographic separation, and LC/MS/MS analysis. The method was fully validated and proved rugged for high-throughput analysis of more than 5000 human plasma samples. Many papers published about this topic describe different methods of sample preparation. Hyotylainen24 has written a recent review. 

Pharmacoiogy Nefazodone is an antidepressant with a chemical structure unrelated to available antidepressant agents. The mechanism of action is unknown. Nefazodone inhibits neuronal uptake of serotonin and norepinephrine. Pharmacokinetics ... 

Disadvantages of nefazodone include the need for a twice-a-day dosing schedule and dose adjustment. Work is under way to develop a once-a-day sustained release version of nefazodone. The fact that nefazodone must be started at a lower than usually effective dose and then adjusted to an effective dose is a distinct disadvantage. That is made even more problematic because arguably more variability exists among patients in terms of the optimal dose of nefazodone as far as efficacy and tolerability than for virtually any other antidepressant. Finally, nefazodone produces substantial inhibition of CYP 3A3/4, leading to the potential for adverse pharmacokinetic interactions as well as possible unknown long-term consequences. 

Nefazodone has appreciable nonlinear pharmacokinetics because of its metabolism by and inhibition of CYP3A3/4 ( 313). At doses of 200 mg per day, nefazodone undergoes an extensive first-pass metabolism such that its bioavailability is only approximately 20%. At doses of 400 mg per day, its bioavailability is appreciably higher, as are its plasma drug levels. This phenomenon is most likely due to inhibition of its own first-pass metabolism by CYP 3A/4. For this reason, dose-dependent effects of nefazodone can increase nonlinearly with higher doses. 

Because most antidepressants require oxidative metabolism as a necessary step in their elimination, they can be the target of a pharmacokinetic drug-drug interaction, as well as the cause. The CYP enzymes mediating the biotransformation of the various antidepressants are also shown in Table 7-30. CYP 1A2 and 3A3/4 are induced by anticonvulsants such as barbiturates and carbamazepine. As expected, coadministration of these anticonvulsants has been shown to lower plasma levels of TCAs and would be predicted to have the same effect on nefazodone, sertraline, and venlafaxine. 

Preskorn S. Pharmacodynamics and pharmacokinetics of nefazodone. Wallingford Academy Meeting, London, April 1993. 

Kaul S, Shukla UA, Barbhaiya R. Nonlinear pharmacokinetics of nefazodone after escalating single and multiple oral doses. J Clin Pharmacol 1995 35 830-839. 

Green DS, Dockens RC, Salazar DE, et al. Coadministration of nefazodone and benzodiazepines. I pharmacokinetic assessment [Abstract]. Clin Pharmacol Ther 1994 55 141. 

The first studies of venlafaxine and nefazodone in both children and adolescents examined pharmacokinetics, safety, and tolerability of these agents ( 35, 36). As expected, the clearance was modestly more rapid in children and adolescents for both of these medications when compared with clearance in adults, but the difference was not sufficient to warrant a significant change in the milligram per kilogram daily dose. These studies should be followed up by appropriately designed efficacy studies. 

Magnus RD, Findling R, Preskorn SH, et al. An open-label pharmacokinetic trial of nefazodone in depressed children and adolescents [Abstract], Psychopharmacol Bull 1997 33 550. 

Lam, Y.W., Alfaro, C.L., Ereshefsky, L., and Miller, M., Pharmacokinetic and pharmacodynamic interactions of oral midazolam with ketoconazole, fluoxetine, fluvoxamine, and nefazodone, J. Clin. Pharmacol, 43(11), 1274-1282, 2003. 

Several LC-MS and LC-MS/MS methods were developed in plasma for only one antidepressant and, sometimes, its major metabolite(s) to perform pharmacokinetic, bioavailability, or bioequivalence studies. Analytical methods developed for these purposes require very low LLOQ values and, usually, narrow linear ranges covering the low range of the therapeutic concentrations are validated. In this context, several methodologies were described for the determination of fluoxetine [94, 95, 98-100], paroxetine [44, 71, 85, 101, 102], venlafaxine [48, 61, 64, 86, 103,104], sertraline [62, 68, 83], citalopram [46, 89] and escitalopram [105], mianserine [106, 107], mirtazapine [42], trazodone [84], nefazodone [51, 81], duloxetine [47, 50, 73], and bupropion [43], Deuterated analogues of the analyte of interest or of other drugs were employed by few authors as IS [43, 61, 73, 81, 85, 99] however, in most of these methods, another antidepressant or other therapeutic drug was used for this purpose. 

Drugs that inhibit CYP3A4 inhibit the clearance of terfenadine, an antihistamine that can prolong the QTC interval. This can cause potentially dangerous interactions. In a double-blind, placebo-controlled study of the effect of nefazodone (600 mg/day for 1 week) on the pharmacokinetics of terfenadine (120 mg/day for 14 days) and another antihistamine, loratadine (20 mg/day for 14 days), in 67 healthy volunteers, nefazodone significantly reduced the clearance of terfenadine and prolonged the mean QTC interval (27). In addition, nefazodone produced a similar but smaller decrease in the clearance of loratadine and combined treatment also significantly increased the QTC interval. This effect of nefazodone on... 

Laroudie C, Salazar DE, Cosson JP, Cheuvart B, Istin B, Girault J, Ingrand I, Decourt JP. Pharmacokinetic evaluation of co-administration of nefazodone and lithium in healthy subjects. Eur J Clin Pharmacol 1999 54(12) 923-8. 

Pharmacokinetic and pharmacodynamic interactions of midazolam with fluoxetine, fluvoxamine, nefazodone, and ketoconazole have been investigated in 40 healthy subjects (64). The mean AUC of midazolam was increased 772% by ketoconazole and 444% by nefazodone. However, fluoxetine and fluvoxamine had no significant effects. Nefazodone and ketoconazole caused significant increases in midazolam-related cognitive impairment, reflecting changed midazolam clearance. 

The pharmacokinetic interaction of nefazodone 200 mg bd with steady-state carbamazepine has been investigated in 12 healthy men (103). Nefazodone increased the steady-state plasma AUC of carbamazepine by 23% and reduced the AUC of active carbamazepine-10,ll-epoxide by 20%. The steady-state AUC of nefazodone fell 14-fold and the AUCs of its metabolites (hydroxynefazodone, metachlorophenylpiperazine, and triazoledione) also fell significantly. Thus nefazodone had a small inhibitory effect on carbamazepine metabolism, while carbamazepine greatly increased the metabolism of nefazodone. 

Green DS, Barvhaiya RH. CUnicalpharmacokinetics of nefazodone. Clin Pharmacokinet 1997 33 260-275. 

Salazar DE, Dockens RC, Milbrath RL, Raymond RH, Fulmor IE, Chaikin PC, Uderman HD, Pharmacokinetic and pharmacodynamic evaluation of warfarin and nefazodone coadministration in heal y subjects. J Clin Pharmacol (1995) 35, 730-8. 

Nefazodone did not affect the pharmacokinetics of phenytoin in healthy subjects. 

Nefazodone 200 mg twice daily for 7 days had no elFect on the pharmacokinetics of a single 300-mg dose of phenytoin in healthy subjects, and no changes in vital signs, ECGs or other physical measurements were seen. There was no evidence that a clinically significant interaction was likely. ... 

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