Relative Bioavailability of Orally Administered Fosphenytoin Sodium Injection Compared with Phenytoin Sodium Injection in Healthy Volunteers Kevin A. Kaucher,1,* Nicole M. Acquisto,2 Gauri G. Rao,3 David C. Kaufman,4 Jeff D. Huntress,5 Alan Forrest,3 and Curtis E. Haas2 1
Department of Pharmacy, Denver Health Medical Center, Denver, Colorado; 2Department of Pharmacy, University of Rochester Medical Center, Rochester, New York; 3Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York; 4Department of Surgery, University of Rochester Medical Center, Rochester, New York; 5Department of Pharmacy, Highland Hospital of Rochester, Rochester, New York
STUDY OBJECTIVE To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers. DESIGN Open-label, randomized, single-dose, two-period, two-sequence crossover study. SETTING University-affiliated clinical research center funded by the National Center of Research Resources. SUBJECTS Ten healthy adult volunteers. INTERVENTION Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400 mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after dose administration. After a 7–14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT). MEASUREMENTS AND MAIN RESULTS The mean age and weight of the 10 subjects were 37 years and 72.5 kg, respectively, and the mean dose was 5.6 mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07–1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0–19.4) mg/L versus 5.0 (3.2–8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5–2.0) hours versus 6.0 (2.0–24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported.
Partial funding for this study was provided by grant UL1 RR 024160 from the National Center for Research Resources, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. Results of this study were presented at the American College of Clinical Pharmacy Annual Meeting, Pittsburgh, Pennsylvania, October 19, 2011. *Address for correspondence: Kevin A. Kaucher, Department of Pharmacy, Denver Health Medical Center, 790 Delaware Street, MC 0056, Denver, CO 80204; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
BIOAVAILABILITY OF ORAL FOSPHENYTOIN Kaucher et al
483
CONCLUSION FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted. KEY WORDS phenytoin sodium solution, phenytoin acid suspension, fosphenytoin sodium solution, bioavailability. (Pharmacotherapy 2015;35(5):482–488) doi: 10.1002/phar.1589
A well-known drug-nutrient interaction exists between oral phenytoin (PHT) acid suspension and enteral nutritional products.1,2 The clinical implications of this interaction are decreased bioavailability of PHT due to suboptimal absorption, resulting in increased risk of treatment failure due to subtherapeutic concentrations. The management of this clinically relevant drug– nutrient interaction has presented multiple challenges to the safe use of enteral PHT in patients receiving continuous enteral feedings. Our previous research evaluated the comparative absolute bioavailability of oral PHT acid suspension and intravenous PHT sodium solution given enterally to healthy subjects also receiving continuous enteral tube feedings.3 Although the average absolute bioavailability for PHT sodium solution and PHT acid suspension were not significantly different (mean SD 0.91 0.7 for PHT sodium solution vs 0.88 0.15 for PHT acid suspension, p=0.57), the PHT acid suspension was associated with much greater variability in bioavailability (F = 4.44, p
Department of Pharmacy, Denver Health Medical Center, Denver, Colorado; 2Department of Pharmacy, University of Rochester Medical Center, Rochester, New York; 3Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York; 4Department of Surgery, University of Rochester Medical Center, Rochester, New York; 5Department of Pharmacy, Highland Hospital of Rochester, Rochester, New York
STUDY OBJECTIVE To describe the pharmacokinetics of fosphenytoin (FPHT) sodium injection when administered orally, and to determine the relative oral bioavailability (FREL) of FPHT sodium injection compared with PHT sodium injection based on pharmacokinetic modeling in healthy volunteers. DESIGN Open-label, randomized, single-dose, two-period, two-sequence crossover study. SETTING University-affiliated clinical research center funded by the National Center of Research Resources. SUBJECTS Ten healthy adult volunteers. INTERVENTION Subjects were randomized to receive a single oral dose of either PHT sodium injection or FPHT sodium injection at a dose equivalent to 400 mg PHT acid. Blood samples were collected at baseline (just prior to administration) and at 0.5, 1, 2, 4, 6, 12, 24, 48, and 72 hours after dose administration. After a 7–14-day washout period, the subjects underwent the same study procedures for administration of the other agent (PHT or FPHT). MEASUREMENTS AND MAIN RESULTS The mean age and weight of the 10 subjects were 37 years and 72.5 kg, respectively, and the mean dose was 5.6 mg/kg based on PHT acid equivalence. The mean FREL of FPHT was 1.21 (95% confidence interval [CI] 1.07–1.35). Serum PHT concentrations were determined by fluorescence polarization immunoassay. The median (range) maximum serum concentration (Cmax) values were significantly higher after FPHT administration compared with PHT: 10.7 (9.0–19.4) mg/L versus 5.0 (3.2–8.9) mg/L (p=0.002). The PHT concentration after oral administration of FPHT displayed faster absorption compared with PHT, with a median (range) time to reach Cmax of 1.0 (0.5–2.0) hours versus 6.0 (2.0–24.0) hours (p=0.008). All subjects completed the study without any serious adverse events reported.
Partial funding for this study was provided by grant UL1 RR 024160 from the National Center for Research Resources, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. Results of this study were presented at the American College of Clinical Pharmacy Annual Meeting, Pittsburgh, Pennsylvania, October 19, 2011. *Address for correspondence: Kevin A. Kaucher, Department of Pharmacy, Denver Health Medical Center, 790 Delaware Street, MC 0056, Denver, CO 80204; e-mail: [email protected]. Ó 2015 Pharmacotherapy Publications, Inc.
BIOAVAILABILITY OF ORAL FOSPHENYTOIN Kaucher et al
483
CONCLUSION FPHT sodium injection given orally was absorbed more rapidly and to a significantly greater extent than PHT sodium injection given orally to healthy volunteers. Further evaluation of oral FPHT as an alternative in patients requiring enteral feedings is warranted. KEY WORDS phenytoin sodium solution, phenytoin acid suspension, fosphenytoin sodium solution, bioavailability. (Pharmacotherapy 2015;35(5):482–488) doi: 10.1002/phar.1589
A well-known drug-nutrient interaction exists between oral phenytoin (PHT) acid suspension and enteral nutritional products.1,2 The clinical implications of this interaction are decreased bioavailability of PHT due to suboptimal absorption, resulting in increased risk of treatment failure due to subtherapeutic concentrations. The management of this clinically relevant drug– nutrient interaction has presented multiple challenges to the safe use of enteral PHT in patients receiving continuous enteral feedings. Our previous research evaluated the comparative absolute bioavailability of oral PHT acid suspension and intravenous PHT sodium solution given enterally to healthy subjects also receiving continuous enteral tube feedings.3 Although the average absolute bioavailability for PHT sodium solution and PHT acid suspension were not significantly different (mean SD 0.91 0.7 for PHT sodium solution vs 0.88 0.15 for PHT acid suspension, p=0.57), the PHT acid suspension was associated with much greater variability in bioavailability (F = 4.44, p
