Phenytoin prodrug 3‐phosphoryloxymethyl phenytoin (ACC‐9653)

Pharmacokinetics in patients following intravenous and intramuscular administration

Bradley Boucher, Anne M. Bombassaro, Soren N. Rasmussen, Ramanuj Achari, Clarence B. Watridge, Prasad Turlapaty

Research output: Contribution to journalArticle

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Abstract

A phenytoin prodrug, 3‐phosphoryloxymethyl phenytoin (ACC‐9653; 1), has been developed with more favorable physicochemical properties than phenytoin for parenteral administration. The purpose of this study was to evaluate the pharmacokinetic profile of 1 following iv and im administration in adult patients receiving chronic oral phenytoin monotherapy. Each patient (9 males, 1 female) received a single iv dose of undiluted 1 equivalent to their twice daily phenytoin dose (100–200 mg) An equivalent dose of im 1 was administered in the gluteus maximus muscle one week later. Serial blood samples were obtained after each dose. Phenytoin and 1 concentrations were measured using HPLC. Compartmental analysis using weighted nonlinear least squares, and noncompartmenta, pharmacokinetic analysis were performed on each patient's concentration–time data. Data following iv 1 in eight of ten patients were best described using a two‐compartment model. Mean pharmacokinetic parameter estimates for iv 1 in these patients were central volume of distribution (Vdc) of 0.040 ± 0.0084 L/kg and plasma disappearance half‐life (t1/2 α) of 8.0 ± 2.9 min (“conversion” t1/2). Overall mean clearance (CL) was 0.24 ± 0.080 L/kg h in the 10 patients. Mean pharmacokinetic parameter estimates for im 1 were a rate constant (ka) of 2.47 ± 1.41 h 1 and an absolute bioavailability (F) of 100.5 ± 20.3%. Mean observed tmax values for phenytoin were 0.57 ± 0.26 and 1.46 ± 0.76 h following iv and im 1, respectively. Model‐independent estimates of clearance agreed well with the compartmental analyses. Steady‐state predose phenytoin concentrations did not significantly vary from the comparable concentrations following iv 1 administration (p = 0.22). Predose phenytoin concentrations were slightly lower following im 1 administration relative to steady‐state phenytoin concentrations (p<0.05). These data demonstrate that the phenytoin prodrug 1 is rapidly converted to phenytoin following single‐dose iv administration in patients. Absorption of im 1 in patients is rapid and relatively complete. The phenytoin prodrug appears to be approximately bioequivalent to oral maintenance doses of phenyton following single iv and im dosing.

Original languageEnglish (US)
Pages (from-to)929-932
Number of pages4
JournalJournal of Pharmaceutical Sciences
Volume78
Issue number11
DOIs
StatePublished - Jan 1 1989

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Prodrugs
Phenytoin
Intravenous Administration
Pharmacokinetics
Least-Squares Analysis
Biological Availability
Half-Life
High Pressure Liquid Chromatography

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

Phenytoin prodrug 3‐phosphoryloxymethyl phenytoin (ACC‐9653) : Pharmacokinetics in patients following intravenous and intramuscular administration. / Boucher, Bradley; Bombassaro, Anne M.; Rasmussen, Soren N.; Achari, Ramanuj; Watridge, Clarence B.; Turlapaty, Prasad.

In: Journal of Pharmaceutical Sciences, Vol. 78, No. 11, 01.01.1989, p. 929-932.

Research output: Contribution to journalArticle

Boucher, Bradley ; Bombassaro, Anne M. ; Rasmussen, Soren N. ; Achari, Ramanuj ; Watridge, Clarence B. ; Turlapaty, Prasad. / Phenytoin prodrug 3‐phosphoryloxymethyl phenytoin (ACC‐9653) : Pharmacokinetics in patients following intravenous and intramuscular administration. In: Journal of Pharmaceutical Sciences. 1989 ; Vol. 78, No. 11. pp. 929-932.
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abstract = "A phenytoin prodrug, 3‐phosphoryloxymethyl phenytoin (ACC‐9653; 1), has been developed with more favorable physicochemical properties than phenytoin for parenteral administration. The purpose of this study was to evaluate the pharmacokinetic profile of 1 following iv and im administration in adult patients receiving chronic oral phenytoin monotherapy. Each patient (9 males, 1 female) received a single iv dose of undiluted 1 equivalent to their twice daily phenytoin dose (100–200 mg) An equivalent dose of im 1 was administered in the gluteus maximus muscle one week later. Serial blood samples were obtained after each dose. Phenytoin and 1 concentrations were measured using HPLC. Compartmental analysis using weighted nonlinear least squares, and noncompartmenta, pharmacokinetic analysis were performed on each patient's concentration–time data. Data following iv 1 in eight of ten patients were best described using a two‐compartment model. Mean pharmacokinetic parameter estimates for iv 1 in these patients were central volume of distribution (Vdc) of 0.040 ± 0.0084 L/kg and plasma disappearance half‐life (t1/2 α) of 8.0 ± 2.9 min (“conversion” t1/2). Overall mean clearance (CL) was 0.24 ± 0.080 L/kg h in the 10 patients. Mean pharmacokinetic parameter estimates for im 1 were a rate constant (ka) of 2.47 ± 1.41 h 1 and an absolute bioavailability (F) of 100.5 ± 20.3{\%}. Mean observed tmax values for phenytoin were 0.57 ± 0.26 and 1.46 ± 0.76 h following iv and im 1, respectively. Model‐independent estimates of clearance agreed well with the compartmental analyses. Steady‐state predose phenytoin concentrations did not significantly vary from the comparable concentrations following iv 1 administration (p = 0.22). Predose phenytoin concentrations were slightly lower following im 1 administration relative to steady‐state phenytoin concentrations (p<0.05). These data demonstrate that the phenytoin prodrug 1 is rapidly converted to phenytoin following single‐dose iv administration in patients. Absorption of im 1 in patients is rapid and relatively complete. The phenytoin prodrug appears to be approximately bioequivalent to oral maintenance doses of phenyton following single iv and im dosing.",
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