Single oral loading dose of phenytoin: a pharmacokinetics study

Ratanakorn, Disya; Kaojarern, Sming; Phuapradit, P; Mokkhavesa, Chintana

doi:10.1016/s0022-510x(96)05314-2

Cited by 16 publications

(16 citation statements)

References 8 publications

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“…[7][8][9][12][13][14] In previous studies, where accelerated oral loading regimens were used (using doses higher than those recommended by the manufacturer), only in one were therapeutic concentrations achieved faster than in the current study. The slower and incomplete absorption that occurs with larger single doses is presumably the result of the capacity-limited absorption of phenytoin.…”

Section: Discussionmentioning

confidence: 99%

“…The slower and incomplete absorption that occurs with larger single doses is presumably the result of the capacity-limited absorption of phenytoin. [6][7][8][9]13 In addition, some authors have reported a higher incidence of ADEs when using higher-than-recommended doses. 7,8,11 To the best of our knowledge, this study is the first to prospectively evaluate ADEs using three common loading techniques of phenytoin in the nonseizing ED patient.…”

Section: Discussionmentioning

confidence: 99%

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A Comparison of Phenytoin-loading Techniques in the Emergency Department

Swadron

Rudis²,

Azimian

et al. 2004

Acad Emergency Med

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Objectives: To compare the effectivenesses of three phenytoin-loading techniques. Methods: Patients with subtherapeutic phenytoin concentrations who presented within 48 hours of a seizure were randomized to receive either 20 mg/ kg of oral phenytoin (PO), divided in maximum doses of 400 mg every two hours, 18 mg/kg of intravenous phenytoin (IVP) at an initial infusion rate of 50 mg/min, or 18 mg/kg (phenytoin equivalents) of intravenous fosphenytoin (IVF) at an initial infusion rate of 150 mg/min. Results: A total of 45 patients were enrolled: 16 in the PO group, 14 in the IVP group, and 15 in the IVF group. The times required to reach therapeutic drug concentrations were (mean 6 standard deviation [SD]) 5.62 6 0.28 hours, 0.24 6 0.3 hours, and 0.21 6 0.28 hours, respectively. A total of 17, 27, and 32 adverse drug events were observed in the PO, IVP, and IVF groups, respectively, with significantly fewer events in the PO group (p ¼ 0.02, p ¼ 0.01). No significant difference was found between the numbers of necessary adjustments to the infusions in the two IV groups. The average time to safe emergency department discharge was significantly shorter for the IV groups compared with the PO group (p\0.001). Conclusions: Oral loading has fewer adverse drug events than either IV loading method, but its use may be limited when therapeutic concentrations are required quickly. Although IVF loading is faster, from an adverse-drug event perspective, no advantage of IVF over IVP was apparent.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Comparison of Phenytoin-loading Techniques in the Emergency Department

Swadron

Rudis²,

Azimian

et al. 2004

Acad Emergency Med

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“…These parameter estimates were then fixed and used during the modeling of free phenytoin concentrations. Based on a review of literature and given the sparse nature of total phenytoin data, a 1-compartment PK model with first-order absorption and nonlinear clearance was evaluated using the ADVAN13 subroutine 22–28 . (22-28) Based on a published population PK model 23 (23), two types of kinetics were tested to describe the nonlinear clearance of phenytoin: 1) Michaelis-Menten kinetics or 2) first-order kinetics in parallel with Michaelis-Menten kinetics.…”

Section: Methodsmentioning

confidence: 99%

Use of Therapeutic Drug Monitoring, Electronic Health Record Data, and Pharmacokinetic Modeling to Determine the Therapeutic Index of Phenytoin and Lamotrigine

Greenberg

et al. 2016

Therapeutic Drug Monitoring

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Background Defining a drug's therapeutic index (TI) is important for patient safety and regulating the development of generic drugs. For many drugs, the TI is unknown. A systematic approach was developed to characterize the TI of a drug using therapeutic drug monitoring and electronic health record (EHR) data with pharmacokinetic (PK) modeling. This approach was first tested on phenytoin, which has a known TI, and then applied to lamotrigine, which lacks a defined TI. Methods Retrospective EHR data from patients in a tertiary hospital were used to develop phenytoin and lamotrigine population PK models and to identify adverse events (anemia, thrombocytopenia, and leukopenia) and efficacy outcomes (seizure-free). Phenytoin and lamotrigine concentrations were simulated for each day with an adverse event or seizure. Relationships between simulated concentrations and adverse events and efficacy outcomes were used to calculate the TI for phenytoin and lamotrigine. Results For phenytoin, 93 patients with 270 total and 174 free concentrations were identified. A de novo 1-compartment PK model with Michaelis-Menten kinetics described the data well. Simulated average total and free concentrations of 10-15 and 1.0-1.5 μg/mL were associated with both adverse events and efficacy in 50% of patients, resulting in a TI of 0.7–1.5. For lamotrigine, 45 patients with 53 concentrations were identified. A published 1-compartment model was adapted to characterize the PK data. No relationships between simulated lamotrigine concentrations and safety or efficacy endpoints were seen; therefore, the TI could not be calculated. Conclusions This approach correctly determined the TI of phenytoin but was unable to determine the TI of lamotrigine due to a limited sample size. The use of therapeutic drug monitoring and EHR data to aid in narrow TI drug classification is promising, but it requires an adequate sample size and accurate characterization of concentration–response relationships.

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“…However, many patients remain seizure free at sub-therapeutic levels and toxicity may appear in the therapeutic range. [3] At higher phenytoin levels, even a small increment in dose or change of route of administration can produce disproportionately high plasma concentrations and thus result in toxicity.…”

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confidence: 99%