James H. Fischer

Vancomycin pharmacokinetics in patients with various degrees of renal function.

The influence of age, protein binding, and renal function on the pharmacokinetics of intravenous vancomycin was evaluated in 37 adult patients with various degrees of renal function. Patients were categorized into three groups based on measured creatinine clearance (CLCR): groups 1, 2, and 3 had 24-h CLCRs of greater than 70, 40 to 70, and 10 to 39 ml/min per 1.73 m2, respectively. After 1 h of intravenous infusion, concentrations of vancomycin in serum declined in a biexponential manner in all patients. Diminished renal function in groups 2 and 3 was accompanied by a lower total body vancomycin clearance (CL) (52.6 and 31.3, respectively, versus 98.4 ml/min per 1.73 m2) and a lower renal vancomycin clearance (CLR) (48.2 and 19.8, respectively, versus 88.0 ml/min per 1.73 m2) than in group 1. No significant differences in apparent distribution volume of the central compartment or apparent distribution volume at steady state were observed. Mean serum protein binding of vancomycin was 30% and was not significantly affected by renal function. Stepwise multiple linear regression analysis revealed that CLCR was the strongest predictor of vancomycin CL (r = 0.77, P less than 0.001) and vancomycin CLR (r = 0.87, P less than 0.001). Age did not significantly improve these correlations once CLCR was included. The relationship of vancomycin CL and CLCR was utilized to develop the following equation to dose vancomycin in the majority of renally impaired patients: dose (milligrams per kilogram per 24 h) = 0.227CLCR + 5.67, where CLCR is standardized to milliliters per minute per 70 kg. The practical dosing intervals that the calculated dose can be divided into and administered include 8, 12, 24, and 48 h based on the CLCR of the patient.

Efficacy and Tolerability of the New Antiepileptic Drugs, II: Treatment of Refractory Epilepsy. Report of the TTA and QSS Subcommittees of the American Academy of Neurology and the American Epilepsy Society

Summary:  Purpose: To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs [AEDs; gabapentin (GBP), lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), oxcarbazepine (OXC), levetiracetam (LEV), and zonisamide (ZNS), reviewed in the order in which these agents received approval by the U.S. Food and Drug Administration] in the treatment of children and adults with newly diagnosed partial and generalized epilepsies.

Up-Regulation of UDP-Glucuronosyltransferase (UGT) 1A4 by 17β-Estradiol: A Potential Mechanism of Increased Lamotrigine Elimination in Pregnancy

Oral clearance of lamotrigine, an antiepileptic drug commonly used in pregnant women, is increased in pregnancy by unknown mechanisms. In this study, we show that 17β-estradiol (E2) up-regulates expression of UDP glucuronosyltransferase (UGT) 1A4, the major enzyme responsible for elimination of lamotrigine. Endogenous mRNA expression levels of UGT1A4 in estrogen receptor (ER) α-negative HepG2 cells were induced 2.3-fold by E2 treatment in the presence of ERα expression. E2 enhanced transcriptional activity of UGT1A4 in a concentration-dependent manner in HepG2 cells when ERα was cotransfected. Induction of UGT1A4 transcriptional activity by E2 was also observed in ERα-positive MCF7 cells, which was abrogated by pretreatment with the antiestrogen fulvestrant (ICI 182,780). Analysis of UGT1A4 upstream regions using luciferase reporter assays identified a putative specificity protein-1 (Sp1) binding site (–1906 to –1901 base pairs) that is critical for the induction of UGT1A4 transcriptional activity by E2. Deletion of the Sp1 binding sequence abolished the UGT1A4 up-regulation by E2, and Sp1 bound to the putative Sp1 binding site as determined by a electrophoretic mobility shift assay. Analysis of ERα domains using ERα mutants revealed that the activation function (AF) 1 and AF2 domains but not the DNA binding domain of ERα are required for UGT1A4 induction by E2 in HepG2 cells. Finally, E2 treatment increased lamotrigine glucuronidation in ERα-transfected HepG2 cells. Together, our data indicate that up-regulation of UGT1A4 expression by E2 is mediated by both ERα and Sp1 and is a potential mechanism contributing to the enhanced elimination of lamotrigine in pregnancy.

Fosphenytoin: clinical pharmacokinetics and comparative advantages in the acute treatment of seizures.

Fosphenytoin is a phosphate ester prodrug developed as an alternative to intravenous phenytoin for acute treatment of seizures. Advantages include more convenient and rapid intravenous administration, availability for intramuscular injection, and low potential for adverse local reactions at injection sites. Drawbacks include the occurrence of transient paraesthesias and pruritus at rapid infusion rates, and cost. Fosphenytoin is highly bound (93-98%) to plasma proteins. Saturable binding at higher plasma concentrations accounts for an increase in its distribution volume and clearance with increasing dose and infusion rate. Fosphenytoin is entirely eliminated through metabolism to phenytoin by blood and tissue phosphatases. The bioavailability of the derived phenytoin relative to intravenous phenytoin is approximately 100% following intravenous or intramuscular administration. The half-life for conversion of fosphenytoin to phenytoin ranges from 7-15 minutes. Faster intravenous infusion rates and competitive displacement of derived phenytoin from plasma protein binding sites by fosphenytoin compensate for the expected conversion-related delay in appearance of phenytoin in the plasma. Unbound phenytoin plasma concentrations achieved with intravenous fosphenytoin loading doses of 100-150 or 50-100mg phenytoin sodium equivalents/min are comparable, and achieved at similar times, to those with equimolar doses of intravenous phenytoin at 50 (maximum recommended rate) or 20-40 mg/min, respectively. The rapid achievement of effective concentrations permits the use of fosphenytoin in emergency situations, such as status epilepticus. Following intramuscular administration, therapeutic phenytoin plasma concentrations are observed within 30 minutes and maximum plasma concentrations occur at approximately 30 minutes for fosphenytoin and at 2-4 hours for derived phenytoin. Plasma concentration profiles for fosphenytoin and total and unbound phenytoin in infants and children closely approximate those in adults following intravenous or intramuscular fosphenytoin at comparable doses and infusion rates. Earlier and higher unbound phenytoin plasma concentrations, and thus an increase in systemic adverse effects, may occur following intravenous fosphenytoin loading doses in patients with a decreased ability to bind fosphenytoin and phenytoin (renal or hepatic disease, hypoalbuminaemia, the elderly). Close monitoring and reduction in the infusion rate by 25-50% are recommended when intravenous loading doses of fosphenytoin are administered in these patients. The potential exists for clinically significant interactions when fosphenytoin is coadministered with other highly protein bound drugs. The pharmacokinetic properties of fosphenytoin permit the drug to serve as a well tolerated and effective alternative to parenteral phenytoin in the emergency and non-emergency management of acute seizures in children and adults.

Valproic acid pharmacokinetics in children. IV. Effects of age and antiepileptic drugs on protein binding and intrinsic clearance

Pharmacokinetic data from 48 children who were taking valproic acid were analyzed by multiple step‐wise linear regression. Children who were receiving enzyme‐inducing antiepileptic drugs (n = 27) had greater (p < 0.01) clearances, elimination rates, and dosage requirements and greater (p < 0.05) variability in pharmacokinetic values than patients receiving monotherapy. Age and polytherapy explained most of the interpatient variability in total (r2 = 0.80; p < 0.001) and intrinsic (r2 = 0.77; p < 0.001) clearances and the elimination rate (r2 = 0.61; p < 0.002). Free fraction variability was related to valproate concentration and phenobarbital (r2 = 0.47; p < 0.001). Distribution volume variance was associated with free fraction (r2 = 0.48; p < 0.001). The effect of age and polytherapy on valproate clearance is primarily attributable to changes in metabolism rather than in protein binding. Valproic acid dosage requirements are greater and more variable for children who are receiving other enzyme‐inducing antiepileptic drugs.

Regulation of UDP-glucuronosyltransferase (UGT) 1A1 by progesterone and its impact on labetalol elimination

The authors recently reported the increased oral clearance of labetalol in pregnant women. To elucidate the mechanism of the elevated oral clearance, it was hypothesized that female hormones, at the high concentrations attainable during pregnancy, enhance hepatic metabolism of labetalol. Labetalol glucuronidation, which is the major elimination pathway of labetalol, was characterized by screening six recombinant human UGTs (UGT1A1, 1A4, 1A6, 1A9, 2B4, and 2B7) for their capacity to catalyse labetalol glucuronidation. The effect of female hormones (progesterone, oestradiol, oestriol, or oestrone) on the promoter activities of relevant UDP glucuronosyltransferases (UGT) was investigated using a luciferase reporter assay in HepG2 cells. The involvement of oestrogen receptor α (ERα) and pregnane X receptor (PXR) was examined by co-transfecting ERα- or PXR-constructs. UGT1A1 and UGT2B7 were identified as the major UGT enzymes producing labetalol glucuronides (trace amount of glucuronide conjugate was formed by UGT1A9). The activities of the UGT1A1 promoter containing PXR response elements were enhanced by progesterone, but not by oestrogens, indicating PXR-mediated induction of UGT1A1 promoter activity by progesterone. Results from semi-quantitative real-time polymerase chain reaction (PCR) assays are consistent with the above findings. This effect of progesterone on UGT1A1 promoter activities was concentration dependent. Promoter activities of UGT2B7 were not affected by either oestrogens or progesterone. The results suggest a potential role for progesterone in regulating labetalol elimination by modulating the expression of UGT1A1, leading to enhanced drug metabolism during pregnancy.

Gabapentin: A New Agent for the Management of Epilepsy

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of gabapentin, a new antiepileptic drug (AED). Gabapentins potential role in the treatment of epilepsy also was assessed. DATA SOURCE: A MEDLINE search was performed to identify all published literature (manuscripts and abstracts). Abstracts presented at the American Epilepsy Society, International Epilepsy Congress, and American Academy of Neurology meetings from 1991 to 1993 also were reviewed. A copy of the proceedings from the Food and Drug Administration Peripheral and Central Nervous System Advisory Committee meeting and package insert were obtained from Parke Davis. STUDY SELECTION: All pertinent literature was reviewed. Emphasis was placed on published information, particularly placebo-controlled clinical trials. DATA SYNTHESIS: Gabapentin is effective as adjunctive treatment for patients with partial seizures with or without secondary generalization refractory to the standard AEDs. It has a unique pharmacokinetic profile for an AED, including no binding to plasma proteins, primary elimination by the kidney, and dose-dependent oral absorption at high dosages. No drug interactions occur with the other AEDs. The most frequent adverse reactions noted in patients receiving gabapentin have been mild and transient central nervous system effects. No serious hypersensitivity or systemic reactions have been observed. CONCLUSIONS: Gabapentin appears to be a useful new AED. Further studies evaluating its use as monotherapy, in higher dosages, and in pediatric and elderly patients are required to better delineate its therapeutic role relative to that of other AEDs.

Saturable transport of gabapentin at the blood-brain barrier

Gabapentin readily crosses the blood-brain barrier and concentrates in brain tissue via an active transport process believed to be system-L. Blood-brain barrier system-L has a low K(m), making it particularly susceptible to substrate saturation. The purpose of this study was to determine whether the fraction of gabapentin crossing the blood-brain barrier remains constant over a broad range of doses. Using a rat model, microdialysis techniques were employed to determine if fluctuations in gabapentin concentrations in the brain extracellular fluid (ECF) coincided with proportional changes in plasma concentrations. Area under the concentration-time curve was calculated for plasma (AUCplasma) and brain extracellular fluid (AUCECF). The ratios of AUFECF to AUCplasma (AUCratio) and brain extracellular fluid to midpoint plasma gabapentin concentration for each collection interval (Cratio) were determined to provide indicators of the relative (i.e. fractional) amount of gabapentin crossing the blood-brain barrier. Analysis of the association between AUCECF and AUCplasma using linear regression analysis revealed a small, but significant relationship (r = 0.62; p < 0.01). Although higher AUCECF values were obtained with higher AUCplasma values, changes in AUCECF were less than proportional to observed changes in AUCplasma. Blood-brain barrier saturation of gabapentin transport was evident as the AUCratio decreased with increased AUCplasma. Collectively, these results support a trend towards saturation at higher plasma concentrations of the carrier-mediated transport mechanism of gabapentin through the blood-brain barrier.

Evaluation of topical metronidazole gel in acne rosacea.

Topical metronidazole gel (0.75%) was compared to placebo gel in a randomized, double-blind, placebo-controlled, split-face clinical trial for the treatment of 59 patients with acne rosacea. Statistically significant differences in inflammatory lesions, erythema, and global assessments were seen at three, six, and nine weeks post-baseline in favor of the active treatment side. It did not, however, alter the telangiectatic component of the disease. No known drug-related side effects were detected, and the low topical dose along with low serum levels of metronidazole indicate a high safety profile for this therapeutic agent. This work suggests that metronidazole gel, as specifically formulated, is safe and effective in reducing the symptomatology of acne rosacea.

Pharmacokinetics of Intravaginal Metronidazole Gel

The pharmacokinetics of a single 500 mg oral dose of metronidazole and 5 g of 0.75% metronidazole intravaginal gel (37.5 mg metronidazole) were compared in 12 adult volunteers in a randomized crossover manner. Serial serum samples were collected over a 48‐hour period and analyzed for metronidazole and hydroxymetronidazole. Metronidazole serum concentrations after intravaginal administration were only 2% of concentrations seen with the standard 500‐mg oral dose. The dose‐adjusted maximum serum concentration (898 ± 121 ng/mL vs. 237 ± 69 ng/mL) and area under the serum concentration—time curve (9362 ± 2873 ng * hr/mL vs. 4977 ± 2671 ng * hr/mL) were significantly greater for the oral versus intravaginal dose of metronidazole. The time to reach maximum concentration (1.4 ± 0.6 hr vs. 8.4 ± 2.2 hr) was significantly shorter for the oral compared with the intravaginal dose. The mean bioavailability for the intravaginal gel was 56%. Our results show that the 0.75% gel formulation may offer the advantage of fewer systemic adverse effects compared with other formulations for the treatment of bacterial vaginosis.