Alan R. Kugler

A saturable transport mechanism in the intestinal absorption of gabapentin is the underlying cause of the lack of proportionality between increasing dose and drug levels in plasma.

Gabapentin (l-(aminomethyl)cyclohexaneacetic acid) is a neuroprotective agent with antiepileptic properties. The structure is small (molecular weight less than 200), is zwitterionic, and resembles an amino acid with the exception that it does not contain a chiral carbon and the amino group is not alpha to the carboxylate functionality. Gabapentin is not metabolized by humans, and thus, the amount of gabapentin excreted by the renal route represents the fraction of dose absorbed. Clinical trials have reported dose-dependent bioavailabilities ranging from 73.8 ± 18.3 to 35.7 ± 18.3% when the dose was increased from 100 to 1600 mg. The permeability of gabapentin in the rat intestinal perfusion system was consistent with carrier-mediated absorption, i.e., a 75 to 80% decrease in permeability when the drug concentration was increased from 0.01 to 50 mM (0.46 ± 0.05 to 0.12 ± 0.04). Excellent agreement was obtained between the actual clinical values and the predicted values from in situ results for the fraction of dose absorbed calculated using the theoretically derived correlation, Fabs = 1 - exp(−2Peff) by Ami-don et al. (Pharm. Res. 5:651–654, 1988). The permeability values obtained for gabapentin correspond to 67.4 and 30.2% of the dose absorbed at the low and high concentrations, respectively. In the everted rat intestinal ring system, gabapentin shared an inhibition profile similar to that of L-phenylalanine. Characteristics of gabapentin uptake included cross-inhibition with L-Phe, sensitivity to inhibition by L-Leu, stereoselectivity as evidenced by incomplete inhibition by D-Phe, and lack of effect by Gly. Our findings support absorption of gabapentin by a saturable pathway, system L, shared by the large hydrophobic amino acids, L-Phe and L-Leu. The saturable absorption pathway makes a major contribution to the lack of proportionality in plasma levels of drug with increasing dose ob-served in the clinic.

Pharmacology and pharmacokinetics of fosphenytoin

Fosphenytoin sodium, a phosphate ester prodrug of phenytoin, was developed as a replacement for parenteral phenytoin sodium.Unlike phenytoin, fosphenytoin is freely soluble in aqueous solutions, including standard IV solutions, and is rapidly absorbed by the IM route. Fosphenytoin is metabolized (conversion half-life of 8 to 15 min) to phenytoin by endogenous phosphatases. Therapeutic free (unbound) and total plasma phenytoin concentrations are consistently attained after IM or IV administration of fosphenytoin loading doses. Fosphenytoin has fewer local adverse effects (e.g., pain, burning, and itching at the injection site) after IM or IV administration than parenteral phenytoin. Systemic effects related to the CNS are similar for both preparations, but transient paresthesias are more common with fosphenytoin. NEUROLOGY 1996;46(Suppl 1): S3-S7

The safety, tolerability, and pharmacokinetics of fosphenytoin after intramuscular and intravenous administration in neurosurgery patients.

Study Objective. To evaluate the safety, tolerability, and pharmacokinetic profile of fosphenytoin, a water‐soluble phenytoin prodrug, after intramuscular and intravenous administration.

Clinical Experience With Fosphenytoin in Adults: Pharmacokinetics, Safety, and Efficacy

Fosphenytoin, a prodrug of phenytoin, is rapidly and completely converted to phenytoin in adults after intravenous or intramuscular administration and is significantly better tolerated than parenteral phenytoin. Fosphenytoin is highly plasma-protein bound and, when present in sufficient concentration, will displace phenytoin from plasma proteins. The clinical utility is that fosphenytoin may be used to achieve therapeutic phenytoin concentrations more rapidly than intravenous phenytoin infused at its maximum recommended rate. In a clinical study of generalized convulsive status epilepticus, fosphenytoin, with or without benzodiazepine pretreatment, controlled seizures in 76 (93.8%) of 81 patients. In other studies, fosphenytoin maintained seizure control when substituted for oral phenytoin and for seizure prophylaxis in neurosurgery and trauma patients. Adverse events associated with fosphenytoin generally were related to the central nervous system and were similar to those associated with phenytoin, except for a higher incidence of transient pruritus with fosphenytoin. Intravenous fosphenytoin has significant advantages over intravenous phenytoin: It requires a shorter infusion time and fewer intravenous disruptions, causes less pain and burning at the infusion site and minimal consequences in case of intravenous infiltration, allows longer maintenance of intravenous sites, and has better intravenous fluid compatibility and stability. In contrast to intramuscular phenytoin, intramuscular fosphenytoin is well tolerated in both large loading doses and maintenance doses. (J Child Neurol 1998;13(Suppl 1):S15-S18).

Pharmacokinetics of Fosphenytoin in Patients with Hepatic or Renal Disease

Summary: 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.

Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of naloxegol at peripheral and central nervous system receptors in healthy male subjects: A single ascending-dose study.

This randomized, double‐blind, placebo‐controlled, ascending‐dose, crossover study evaluated single oral doses of naloxegol (NKTR‐118; 8, 15, 30, 60, 125, 250, 500, and 1000 mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol‐matching placebo administered with morphine and lactulose in a 2‐period crossover design. Periods were separated by a 5‐ to 7‐day washout. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine‐induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose‐ordered antagonism of morphines peripheral gastrointestinal effects. Forty‐four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000 mg, indicating negligible antagonism of morphines CNS effects at doses ≤ 125 mg. Rapid absorption, linear pharmacokinetics up to 1000 mg, and low to moderate between‐subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000 mg.

Safety, tolerability, and pharmacokinetics of multiple ascending doses of naloxegol.

Opioid‐induced constipation (OIC) is the most common and often a treatment‐limiting adverse event (AE) of opioid therapy for chronic pain. Naloxegol (previously NKTR‐118), a PEGylated derivative of naloxone that has minimal penetration of the central nervous system, has received regulatory approval as an oral therapy for OIC. This randomized, double‐blind, placebo‐controlled, multiple‐dose, dose‐escalation study was performed to assess safety, tolerability, and pharmacokinetics of multiple doses of naloxegol in healthy volunteers. Four cohorts, each with 4 male and 4 female volunteers, were randomized 3:1 to a twice‐daily naloxegol solution (25, 60, 125, and 250 mg) or matching placebo solution. Doses were given every 12 hours for 7 days, with a single final dose on the morning of day 8. All 32 subjects completed the study. The incidence of most AEs was similar in the naloxegol and placebo groups; no AE led to study discontinuation. Naloxegol was rapidly absorbed. Plasma naloxegol pharmacokinetics showed dose proportionality, negligible accumulation at steady state, and no sex differences. Naloxegol in doses up to 250 mg every 12 hours was generally safe and well tolerated in this healthy volunteer population.

CLINICAL PHARMACOKINETICS OF FOSPHENYTOIN: AN OVERVIEW

BACKGROUND- Fosphenytoin is a water-soluble prodrug of phenytoin that can be administered by intramuscular (IM) injection or as a slow or fast intravenous (IV) infusion. In this article, we review the pharmacokinetics of fosphenytoin and phenytoin derived from its administration.SUMMARY- Fosphenytoin is completely bioavailable after IV or IM injection, although peak plasma fosphenytoin concentrations achieved through IM administration are lower and more sustained than those that follow IV administration. Fosphenytoin resides predominantly in the plasma compartment (volume of distribution 0.13 L/kg), where it is extensively bound to the same plasma proteins as phenytoin, which leads to displacement of phenytoin, particularly after the rapid administration of high fosphenytoin doses. Fosphenytoin is rapidly converted to phenytoin (conversion half-life 10 to 15 minutes), and fosphenytoin doses and infusion rates are expressed in phenytoin equivalents. Phosphate and formate are also generated in this reaction but do not result in any adverse metabolic consequences. After the IV administration of equivalent loading doses of fosphenytoin and phenytoin at their maximal recommended infusion rates, therapeutic plasma phenytoin concentrations are achieved significantly faster in subjects who receive fosphenytoin. Patient sex and race have no effect on fosphenytoin pharmacokinetics. Clearance of phenytoin produced from fosphenytoin increases with advancing age. Fosphenytoin free fraction and clearance to phenytoin are increased in patients with renal or hepatic disease.CONCLUSIONS- Data from extensive pharmacokinetics studies indicate that modification of the fosphenytoin loading dose due to demographic factors is not necessary in most patients, although individualization of the dosing regimen should be based on factors used to guide phenytoin administration. Rapid infusion of fosphenytoin loading doses (150 mg/min) is indicated in clinical settings in which rapid achievement of therapeutic phenytoin concentrations is critical. Slower infusions (50 to 100 mg/min) or IM administration may be used in nonemergent situations.