Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease

Francesca T. Aweeka, Mildred D. Gottwald, John G. Gambertoglio, Teresa L. Wright, Thomas D Boyer, Alan S. Pollock, Michael A. Eldon, Alan R. Kugler, Brian K. Alldredge

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Purpose: The pharmacokinetic behavior of fosphenytoin (FOS), the water- soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT. Methods: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). Serial plasma concentrations were measured, and pharmacokinetic parameters were calculated. Results: The mean time to reach the peak plasma FOS concentration was similar for each of the three groups. However, the mean time to achieve peak plasma concentrations of PHT tended to occur earlier in the hepatic or renal disease groups than in healthy subjects. The half-life of FOS was 4.5, 9.2, and 9.5 min for the three groups, respectively. There was a trend toward increased FOS clearance and earlier peak PHT concentration in subjects with hepatic or renal disease. This finding is consistent with decreased binding of FOS to plasma proteins and increased fraction of unbound FOS resulting from decreased plasma protein concentrations associated with these disease states. The conversion of FOS to PHT was equally efficient in subjects with hepatic or renal disease and healthy subjects. Conclusions: Although the differences in pharmacokinetic parameters between the three groups were not statistically significant, these data suggest the need for close clinical monitoring during FOS administration to patients with hepatic or renal disease. To minimize the incidence of adverse effects in this patient population, FOS may need to be administered at lower doses or infused more slowly.

Original languageEnglish (US)
Pages (from-to)777-782
Number of pages6
JournalEpilepsia
Volume40
Issue number6
DOIs
StatePublished - 1999
Externally publishedYes

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Pharmacokinetics
Kidney
Liver
Phenytoin
Healthy Volunteers
fosphenytoin
Prodrugs
Liver Cirrhosis
Half-Life
Renal Dialysis
Blood Proteins
Maintenance
Water
Incidence
Population

Keywords

  • Fosphenytoin
  • Hepatic disease
  • Pharmacokinetics
  • Phenytoin
  • Renal disease

ASJC Scopus subject areas

  • Clinical Neurology
  • Neuroscience(all)

Cite this

Aweeka, F. T., Gottwald, M. D., Gambertoglio, J. G., Wright, T. L., Boyer, T. D., Pollock, A. S., ... Alldredge, B. K. (1999). Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease. Epilepsia, 40(6), 777-782. https://doi.org/10.1111/j.1528-1157.1999.tb00778.x

Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease. / Aweeka, Francesca T.; Gottwald, Mildred D.; Gambertoglio, John G.; Wright, Teresa L.; Boyer, Thomas D; Pollock, Alan S.; Eldon, Michael A.; Kugler, Alan R.; Alldredge, Brian K.

In: Epilepsia, Vol. 40, No. 6, 1999, p. 777-782.

Research output: Contribution to journalArticle

Aweeka, FT, Gottwald, MD, Gambertoglio, JG, Wright, TL, Boyer, TD, Pollock, AS, Eldon, MA, Kugler, AR & Alldredge, BK 1999, 'Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease', Epilepsia, vol. 40, no. 6, pp. 777-782. https://doi.org/10.1111/j.1528-1157.1999.tb00778.x
Aweeka, Francesca T. ; Gottwald, Mildred D. ; Gambertoglio, John G. ; Wright, Teresa L. ; Boyer, Thomas D ; Pollock, Alan S. ; Eldon, Michael A. ; Kugler, Alan R. ; Alldredge, Brian K. / Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease. In: Epilepsia. 1999 ; Vol. 40, No. 6. pp. 777-782.
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abstract = "Purpose: The pharmacokinetic behavior of fosphenytoin (FOS), the water- soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT. Methods: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). Serial plasma concentrations were measured, and pharmacokinetic parameters were calculated. Results: The mean time to reach the peak plasma FOS concentration was similar for each of the three groups. However, the mean time to achieve peak plasma concentrations of PHT tended to occur earlier in the hepatic or renal disease groups than in healthy subjects. The half-life of FOS was 4.5, 9.2, and 9.5 min for the three groups, respectively. There was a trend toward increased FOS clearance and earlier peak PHT concentration in subjects with hepatic or renal disease. This finding is consistent with decreased binding of FOS to plasma proteins and increased fraction of unbound FOS resulting from decreased plasma protein concentrations associated with these disease states. The conversion of FOS to PHT was equally efficient in subjects with hepatic or renal disease and healthy subjects. Conclusions: Although the differences in pharmacokinetic parameters between the three groups were not statistically significant, these data suggest the need for close clinical monitoring during FOS administration to patients with hepatic or renal disease. To minimize the incidence of adverse effects in this patient population, FOS may need to be administered at lower doses or infused more slowly.",
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T1 - Pharmacokinetics of fosphenytoin in patients with hepatic or renal disease

AU - Aweeka, Francesca T.

AU - Gottwald, Mildred D.

AU - Gambertoglio, John G.

AU - Wright, Teresa L.

AU - Boyer, Thomas D

AU - Pollock, Alan S.

AU - Eldon, Michael A.

AU - Kugler, Alan R.

AU - Alldredge, Brian K.

PY - 1999

Y1 - 1999

N2 - Purpose: The pharmacokinetic behavior of fosphenytoin (FOS), the water- soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT. Methods: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). Serial plasma concentrations were measured, and pharmacokinetic parameters were calculated. Results: The mean time to reach the peak plasma FOS concentration was similar for each of the three groups. However, the mean time to achieve peak plasma concentrations of PHT tended to occur earlier in the hepatic or renal disease groups than in healthy subjects. The half-life of FOS was 4.5, 9.2, and 9.5 min for the three groups, respectively. There was a trend toward increased FOS clearance and earlier peak PHT concentration in subjects with hepatic or renal disease. This finding is consistent with decreased binding of FOS to plasma proteins and increased fraction of unbound FOS resulting from decreased plasma protein concentrations associated with these disease states. The conversion of FOS to PHT was equally efficient in subjects with hepatic or renal disease and healthy subjects. Conclusions: Although the differences in pharmacokinetic parameters between the three groups were not statistically significant, these data suggest the need for close clinical monitoring during FOS administration to patients with hepatic or renal disease. To minimize the incidence of adverse effects in this patient population, FOS may need to be administered at lower doses or infused more slowly.

AB - Purpose: The pharmacokinetic behavior of fosphenytoin (FOS), the water- soluble prodrug of phenytoin (PHT), has been characterized in normal subjects. This is the first study of the effect of hepatic or renal disease on the rate and extent of conversion of FOS to PHT. Methods: A single dose of fosphenytoin (250 mg over a period of 30 min) was administered to subjects with hepatic cirrhosis (n = 4), renal disease requiring maintenance hemodialysis (n = 4), and healthy controls (n = 4). Serial plasma concentrations were measured, and pharmacokinetic parameters were calculated. Results: The mean time to reach the peak plasma FOS concentration was similar for each of the three groups. However, the mean time to achieve peak plasma concentrations of PHT tended to occur earlier in the hepatic or renal disease groups than in healthy subjects. The half-life of FOS was 4.5, 9.2, and 9.5 min for the three groups, respectively. There was a trend toward increased FOS clearance and earlier peak PHT concentration in subjects with hepatic or renal disease. This finding is consistent with decreased binding of FOS to plasma proteins and increased fraction of unbound FOS resulting from decreased plasma protein concentrations associated with these disease states. The conversion of FOS to PHT was equally efficient in subjects with hepatic or renal disease and healthy subjects. Conclusions: Although the differences in pharmacokinetic parameters between the three groups were not statistically significant, these data suggest the need for close clinical monitoring during FOS administration to patients with hepatic or renal disease. To minimize the incidence of adverse effects in this patient population, FOS may need to be administered at lower doses or infused more slowly.

KW - Fosphenytoin

KW - Hepatic disease

KW - Pharmacokinetics

KW - Phenytoin

KW - Renal disease

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