Bioavailability Studies of Drugs with Nonlinear Pharmacokinetics: II. Absolute Bioavailability of Intravenous Phenytoin Prodrug at Therapeutic Phenytoin Serum Concentrations Determined by Double‐Stable Isotope Technique

Browne, Thomas R.; Szabó, George; McEntegart, Carol M.; Evans, James E.; Evans, Barbara A.; Miceli, J.; Quon, Check Y.; Dougherty, Carol L.; Kres, Jan; Davoudi, Hamid

doi:10.1002/j.1552-4604.1993.tb03910.x

Cited by 15 publications

(4 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…45 The conversion half-life was 9.3 2 2.7 minutes, which is substantially shorter than that reported in the subsequent 43 A similar half-life was estimated (8.0 * 2.9 min) in another study in which a single dose of intravenous fosphenytoin was admini~tered.~~ In six men with epilepsy receiving oral phenytoin, the estimated half-life was 8.80 2 7.24 minutes after a single dose of intravenous fosphenytoin administered as a stable isotope. 46 The AUC for phenytoin derived from this dose was bioequivalent to that of a n equimolar intravenous dose of a phenytoin sodium stable isotope. The conversion of fosphenytoin to phenytoin did not appear to be affected by preexisting concentrations of phenytoin.…”

Section: Metabolism and Eliminationmentioning

confidence: 87%

Fosphenytoin: A Novel Phenytoin Prodrug

Boucher

1996

Pharmacotherapy

View full text Add to dashboard Cite

Fosphenytoin is a phenytoin prodrug that received an approvable letter from the Food and Drug Administration in February 1996. It was designed to overcome many of the shortcomings associated with parenteral phenytoin sodium. Specifically, fosphenytoin is a highly water‐soluble, phosphate ester of phenytoin that has no known pharmacologic activity before its conversion to phenytoin. Dosing of fosphenytoin uses phenytoin equivalents (PE) to minimize dosage errors when converting from the conventional formulation. Pharmacokinetic studies documented that the agent is rapidly and completely converted to phenytoin after intravenous and intramuscular dosing. Reported conversion half‐lives after intravenous administration range from 8–15 minutes. The absorption rate appears to be the rate‐limiting step in the conversion of fosphenytoin to phenytoin after intramuscular administration (half‐life range 22–41 min). Bioavailability of phenytoin derived from both intravenous and intramuscular fosphenytoin is essentially 100%. As a consequence of concentration‐dependent protein binding, fosphenytoin is bioequivalent to phenytoin sodium at intravenous infusion rates of 100–150 mg PE/minute and 50 mg/minute, respectively. In clinical studies to date, fosphenytoin is safe and significantly better tolerated than phenytoin sodium when administered intravenously. It is also well tolerated when given intramuscularly, and this is a valuable alternative route of administration when intravenous access or cardiographic monitoring is unavailable. Its pharmacoeconomic advantages over phenytoin have not been documented in formal studies to date, although the likelihood of savings based on cost‐effectiveness analyses is high. Hence, fosphenytoin has the potential as a safe, well‐tolerated, and effective means of delivering phenytoin parenterally in a variety of clinical settings.

show abstract

Section: Metabolism and Eliminationmentioning

confidence: 87%

Fosphenytoin: A Novel Phenytoin Prodrug

Boucher

1996

Pharmacotherapy

View full text Add to dashboard Cite

show abstract

“…total/free/conjugated substance levels or blood/urine), consideration should be given to a self‐reference study of several doses of the reference product in order to determine which parameter/matrix may be optimal to assess bioequivalence. Use of surrogate parameters has not been successfully employed in bioequivalence studies of endogenous drugs to date. Nonlinearity is likely to be a frequent issue in bioequivalence studies of endogenous drugs given homeostatic mechanisms, saturable processes, interchangeable substance pools, etc. Therefore, in addition to the concepts described above, the dose most likely to distinguish potency differences should be considered in designing a biostudy to compare such drugs. Consideration should also be given to the dual stable isotope technique to demonstrate bioequivalence between test and reference formulations, a method that has been described for various ‘non‐endogenous’ drugs [25–30]. However, this method, which involves the substitution of chemical elements within the drug molecule by stable isotopes that are not subject to radioactive decay such as 2 H, 13 C or 15 N, is only feasible where isotopes can be incorporated into the chemical structure of both test and reference formulations during the manufacturing process.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, in addition to the concepts described above, the dose most likely to distinguish potency differences should be considered in designing a biostudy to compare such drugs. 10 Consideration should also be given to the dual stable isotope technique to demonstrate bioequivalence between test and reference formulations,a method that has been described for various 'non-endogenous' drugs [25][26][27][28][29][30]. However, this method, which involves the substitution of chemical elements within the drug molecule by stable isotopes that are not subject to radioactive decay such as 2 H, 13 C or 15 N, is only feasible where isotopes can be incorporated into the chemical structure of both test and reference formulations during the manufacturing process.…”

Section: S Dissanayakementioning

confidence: 99%

Assessing the bioequivalence of analogues of endogenous substances (‘endogenous drugs’): considerations to optimize study design

Dissanayake¹

2010

Brit J Clinical Pharma

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The complexities of assessing the bioequivalence of endogenous drugs are recognised. • The FDA have published guidelines regarding the evaluation of levothyroxine and potassium chloride bioequivalence, whilst other authors have documented specific strategies to counter biases inherent in biostudies of endogenous drugs. • A consolidated consideration of valid methods to optimise the design of such studies is however lacking. WHAT THIS STUDY ADDS • This paper is to the author's knowledge the first summarising various key approaches used to assess the bioequivalence of endogenous drugs, and to propose a series of recommendations for studies in this field. BACKGROUND Assessment of the bioequivalence of generic versions of certain reference drugs is complicated by the presence of endogenous levels of said compounds which cannot be distinguished from externally derived compound levels following drug administration. If unaccounted for, the presence of endogenous compound biases towards equivalence in bioequivalence studies of these drugs. Bioequivalence assessments may be complicated further as disposition of the exogenous analogue can be subject to various endogenous processes resulting in nonlinear pharmacokinetics. To overcome these inherent biases a number of different strategies have been employed. AIMS To critically review methods used to overcome confounding biases in bioequivalence studies of ‘endogenous’ drugs. METHODS A literature search of the EMBASE and PubMed databases was performed. RESULTS The following strategies were identified: ablation/modulation of baseline endogenous substance levels; recruitment of ‘substance‐deficient’ populations; restriction of dietary intake of the relevant substance; standardization of conditions with the potential to affect relevant homeostatic mechanisms; correction for baseline substance levels; and administration of supra‐therapeutic drug doses. CONCLUSIONS On the basis of this review key study design concepts, intended to optimize the design of future bioequivalence studies of these so‐called ‘endogenous drugs’, are described. The dual stable isotope method, which could be used in a specific context, is also discussed.

show abstract

“…The conversion half-life is 8–15 min; however, the exact site(s) of conversion has not been determined. The conversion occurs independent of prior phenytoin plasma concentration (Browne et al 1993). Also, no factors have been found that may affect conversion, including race, gender or age.…”

Section: Introductionmentioning

confidence: 99%

Bioavailability of intravenous fosphenytoin sodium in healthy Japanese volunteers

Inoue

Usui

Hiroki³

et al. 2012

Eur J Drug Metab Pharmacokinet

View full text Add to dashboard Cite

To compare and evaluate the bioavailability for intravenous fosphenytoin sodium with that of intravenous phenytoin sodium in Japanese subjects. In study 1, healthy Japanese male volunteers received a 30-min infusion of 375 mg fosphenytoin sodium or an equimolar dose of 250 mg phenytoin by a double-blind, crossover method. In study 2, other healthy Japanese male volunteers received a 30-min or 10-min infusion of 563 mg fosphenytoin sodium, followed by a dose of 750 mg after 2 weeks in an unblinded manner. Comparing with 250 mg phenytoin sodium, 375 mg fosphenytoin sodium exhibited lower total plasma phenytoin Cmax, whereas the geometric mean ratio of the AUC of total and free phenyotoin for fosphenytoin sodium at a dose of 375 mg was very similar to phenytoin sodium at a equimolar dose of 250 mg (AUC0–t ratio: 0.98 and 1.02, respectively). Therefore, fosphenytoin is almost completely converted to phenytoin in subjects. Fosphenytoin sodium was rapidly converted to phenytoin at doses of 375, 563, and 750 mg. The maximum concentration (Cmax) of total plasma phenytoin increased in a dose-dependent manner. The area under the plasma concentration–time curve (AUC) increased slightly more than proportionally with the administered dose, and clearance (CL) decreased with increasing dose. Pain and other infusion-site reactions were reported by all 12 subjects with phenytoin sodium, whereas very few symptoms were observed with fosphenytoin sodium. In conclusion, fosphenytoin sodium is considered to be a useful substitute for phenytoin sodium with almost no associated injection-site reactions.

show abstract

Bioavailability Studies of Drugs with Nonlinear Pharmacokinetics: II. Absolute Bioavailability of Intravenous Phenytoin Prodrug at Therapeutic Phenytoin Serum Concentrations Determined by Double‐Stable Isotope Technique

Cited by 15 publications

References 10 publications

Fosphenytoin: A Novel Phenytoin Prodrug

Fosphenytoin: A Novel Phenytoin Prodrug

Assessing the bioequivalence of analogues of endogenous substances (‘endogenous drugs’): considerations to optimize study design

Bioavailability of intravenous fosphenytoin sodium in healthy Japanese volunteers

Contact Info

Product

Resources

About