Pharmacokinetic Evaluation

A phase 1 trial was carried out in 12 normal volunteers to assess the effect of co-administration of fluvoxamine on the systemic exposure of DDZ following oral administration. In this crossover study, subjects were randomized to receive either DDZ alone (dose = 10 mg, CONTROL) or following pretreatment for four days with fluvoxamine (150 mg/day, INTERACTION). Blood samples were collected for 14 days following administration of DDZ and plasma concentrations were measured by HPLC. There was a 30-day washout period between treatments.

The mean plasma concentration vs time profile for DDZ in the control and interaction phases of the study are provided in the Figure below. A list of DDZ pharmacokinetic parameters resulting from the study are provided in the Table on the next page. DDZ plasma concentration vs time profile in the absence (CONTROL) and presence (INTERACTION) of fluvoxamine.

Table of DDZ Pharmacokinetic Parameters Following Oral Administration (10 mg)

Parameter CONTROL INTERACTION

AUC0-last (ng-hr/mL) 8753 17340

Cmax (ng/mL) 109 164

Clast (ng/mL) 6.22 31.1

t1/2 (hr) 51 118

Please answer the following questions about these results

8. Please fill in the following Table by performing the appropriate calculations based on the information above.

Please indicate the parameter units for each parameter in the far right column

Parameter CONTROL INTERACTION Units

k ? ? ?

AUC0-

Cl/F

V/F

9. What is the likely reason for the observed results of the study? In other words, what is the likely mechanism of the pharmacokinetic interaction between fluvoxamine and DDZ? Please explain briefly.

10. Assuming DDZ was administered as a daily dose (every 24 hours), would you expect plasma levels to accumulation at steady state? Please provide a brief explanation.