Pharmacokinetics and Pharmacodynamics of Nefazodone and Propranolol Co-administration

Abstract

Eighteen healthy male subjects received the following treatments (Q12h for 6.5 days) in randomized order with 14 day washout between periods: nefazodone 200 mg (NEF), propranolol 40 mg (PRO), and co-administration of NEF and PRO (NEF/PRO). Measurements of heart rate (HR) and systolic blood pressure for calculation of double product (DP= HRxSBP), an index of cardiac oxygen demand, were obtained prior to, during and after exercise on a treadmill using a multistage graded exercise protocol on Days 1 (pretreatment) and 6 (2 hr post dose) of each leg. Pharmacokinetics (PK) were evaluated on Day 7. There was no significant effect of NEF treatment on HR or DP compared to pretreatment. PRO and NEF/PRO produced similar decreases in HR at rest and during the exercise protocol. NEF/PRO reduced pre-exercise DP by 21% which was not different than PRO. However, post-exercise DP with NEF/PRO was decreased 40%, compared with the 23% decrease produced by PRO (p<0.05). This difference is not considered clinically significant. There was no effect of co-administration on PK of nefazodone and two metabolites, hydroxynefazodone and triazole dione. However, the AUC0-12 and Cmax of mCPP were increased by 28% and 22% with co-administration. Furthermore, the Cmax and AUC0-12 of propranolol were 30% and 14% lower with NEF/PRO than with PRO, however, there was no change in T-half. Similar changes in the PK of 4-OH propranolol were observed. In conclusion, co-administration of NEF and PRO caused modest changes in the PK of mCPP, propranolol and 4-hydroxypropranolol. However, the suppression of exercise-induced tachycardia and DP produced by PRO were not significantly affected by NEF. Thus, the PK inequivalencies are not clinically significant. Therefore, no change in initial dose of either drug is necessary and dose adjustments should be made on the basis of clinical response.