Jeannine M. Conway

Variability of total phenytoin serum concentrations within elderly nursing home residents.

Background: Approximately 6% of all elderly nursing home residents receive phenytoin. Phenytoin concentrations are often measured to guide therapy. Objective: To evaluate the intraresident variability among multiple measurements of total phenytoin serum concentrations in nursing home residents. Methods: This was an observational study of 56 elderly (≥65 years) nursing home residents from 32 nursing homes who had at least 3 phenytoin concentrations measured while on the same dose of phenytoin for at least 4 weeks and who were not taking any interfering concomitant medications. These were a subset of 387 elderly nursing home residents from 112 nursing homes across the United States who had total phenytoin concentration measurements between June 1998 and December 2000. Results: The mean age was 80.1 years (range, 65 to 100 years) and 58.9% were women. The mean daily dose of phenytoin per resident was 4.9 ± 1.5 mg/kg. Total phenytoin concentrations within an elderly nursing home resident varied as much as two- to threefold, even though there was no change in dose. The person with the smallest variability had a minimum concentration of 10.0 μg/mL and a maximum of 10.4 μg/mL. The person with the largest variability had a minimum concentration of 9.7 μg/mL and a maximum of 28.8 μg/mL. Conclusions: There is considerable variability in the total phenytoin concentrations in the elderly nursing home resident and measurement of a single total phenytoin concentration should not be used to guide treatment.

Steady-State Carbamazepine Pharmacokinetics Following Oral and Stable-Labeled Intravenous Administration in Epilepsy Patients: Effects of Race and Sex

Carbamazepine is a widely prescribed antiepileptic drug. Owing to the lack of an intravenous formulation, its absolute bioavailability, absolute clearance, and half‐life in patients at steady state have not been determined. We developed an intravenous, stable‐labeled (SL) formulation in order to characterize carbamazepine pharmacokinetics in patients. Ninety‐two patients received a 100‐mg infusion of SL‐carbamazepine as part of their morning dose. Blood samples were collected up to 96 hours after drug administration. Plasma drug concentrations were measured with liquid chromatography–mass spectrometry, and concentration–time data were analyzed using a noncompartmental approach. Absolute clearance (l/hr/kg) was significantly lower in men (0.039 ± 0.017) than in women (0.049 ± 0.018; P = 0.007) and in African Americans (0.039 ± 0.017) when compared with Caucasians (0.048 ± 0.018; P = 0.019). Half‐life was significantly longer in men than in women as well as in African Americans as compared with Caucasians. The absolute bioavailability was 0.78. Sex and racial differences in clearance may contribute to variable dosing requirements and clinical response.

Valproic acid doses, concentrations, and clearances in elderly nursing home residents

VPA daily dose and total VPA concentrations for 146 elderly (> or =65 years) nursing home residents collected from June 1998 to December 2000 in homes located throughout the United States are presented. Average age was 78.5+/-8.0 years old. The mean VPA daily dose was 16.2+/-11.2mg/kg and mean total VPA concentration was 48.5+/-24.8 mg/L. The majority (56.2%) of the VPA residents are being maintained at total VPA levels <50mg/L. Mean daily dose (19.4+/-11.4, 16.3+/-12.1, and 11.3+/-7.6 mg/kg/day; p=0.003) and total VPA concentration (56.4+/-25.8, 47.7+/-22.6, and 38.7+/-23.1mg/kg/day; p=0.003) decreased by age groups (65-74, 75-84, and > or =85 years). Daily dose and total VPA concentration were not different in residents receiving inhibitory or inducing co-medications, between men and women, or by albumin level. Total VPA clearance was similar between men and women, among age groups, or according to inducing or inhibiting co-medications.

Population pharmacokinetics of valproic acid concentrations in elderly nursing home residents.

The objective of this study was to identify factors that affect valproic acid (VPA) apparent clearance (CL/F) in elderly nursing home residents. Inclusion criteria included residency in a nursing home for at least 2 months, aged 65 years or older, a stable dosing regimen of VPA for at least 4 weeks, VPA concentration, and complete dosing information. CL/F was analyzed by a nonlinear mixed effects model. A one-compartment model with first-order absorption and elimination was used. Both volume and absorption rate constant were fixed (14 L and 1 hr−1, respectively). Covariates were tested by forward inclusion and backward elimination. Interindividual variability in clearance was estimated using an exponential error model and expressed as a coefficient of variation. Residual error was estimated using a combined additive and constant coefficient of variation error model. The study consisted of 405 observations from 146 (52 men, 94 women) elderly nursing home residents. CL/F was not affected by age or weight. The population CL/F was 0.843 L/hr. CL/F was 1) 27% lower in female residents; 2) 41% greater when the resident was on concomitant metabolic inducers carbamazepine or phenytoin cotherapy; and 3) 25% greater when the syrup formulation was used. Variability in CL/F was 32.9%. Coefficient of variation and standard deviation of the residual error were 18.2% and 10.6 mg/L, respectively. The increased CL/F in patients taking VPA syrup may be the result of a decreased bioavailability (F) rather than an increased CL that could be associated with pathology requiring use of the syrup rather than an inherent property of the drug formulation. The results from this study may be useful for individualizing dose regimens in the nursing home population based on patient-specific factors.

Phenytoin use in elderly nursing home residents.

BACKGROUND Phenytoin (PHT) dosing regimens are often determined based on experience in those aged <65 years rather than in those aged >or=65 years. OBJECTIVE The goal of this study was to determine the impact of sex, age, receipt of concomitant inhibitors or inducers of PHT metabolism, and albumin levels on doses and total serum concentrations of PHT in elderly nursing home residents. METHODS Consulting pharmacists to nursing homes located throughout the United States collected data from June 1998 to December 2000. The mean daily dose per person and mean total serum PHT concentration were tested for statistical differences by sex, age group (6-74, 75-84, and >or=85 years), coadministration of PHT inhibitors or inducers, and albumin levels. RESULTS Data were collected from 387 residents (259 women, 128 men) of 112 nursing homes in 19 states who received PHT and for whom PHT concentrations were available. The mean (SD) age of the study population was 79.4 (7.8) years; women constituted 67.0% of the study population. The mean (SD) total daily dose and total PHT concentration were 4.9 (1.8) mg/kg and 11.7 (6.4) mg/L, respectively. In general, women received higher mean (SD) daily doses of PHT compared with men (5.1 [1.8] vs 4.6 [1.6] mg/kg, respectively; P=0.017) to achieve similar total serum concentrations (11.6 [6.4] and 12.0 [6.6] mg/L). PHT doses and serum concentrations were similar between age groups. There were no differences in daily doses (mg/kg or mg/d) or total serum concentrations of PHT based on concomitant use of inhibitors or inducers of PHT metabolism or on albumin levels, CONCLUSIONS In this study in elderly nursing home residents, women received higher doses of PHT than men to achieve similar total serum PHT concentrations. There were no differences in doses or total serum PHT concentrations by age group, use of concomitant inducers or inhibitors of PHT metabolism, or albumin levels.

Relative bioavailability of topiramate administered rectally

OBJECTIVE To determine the relative bioavailability and tolerability of a topiramate (TPM) suspension after rectal administration. DESIGN/METHOD Seven healthy men and five healthy non-pregnant women were enrolled. A 100 or 200 mg tablet of TPM was given orally and a 200 mg dose was given rectally in a randomized, open-label, crossover study with at least a 2-week washout period between doses. Plasma samples were collected prior to dosing and the following times after each dose: 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, and 96 h. Relative bioavailability was determined by calculating the ratio of the dose-normalized area under the curve (AUC/D) for the rectal and oral doses. RESULTS Ten subjects completed the study. Two of the first seven subjects who received a 200 mg initial oral dose, withdrew because of side effects. The remaining subjects received a 100 mg oral dose. Three subjects received a 200 mg dose orally and rectally, and seven subjects received 100 mg orally and 200mg rectally. The average AUC/D was 0.72+/-0.18 h/l for the rectal dose and 0.76+/-0.20 h/l for the oral dose. The relative bioavailability (n=10) for TPM administered rectally was 0.95+/-0.17 with a range of 0.68-1.2. There were no statistically significant differences between the oral or rectal pharmacokinetic parameters. CONCLUSIONS In healthy adults, rectally administered TPM is absorbed to a similar extent as the oral dosage form. Rectal administration is an acceptable route of administration for TPM, when the oral route is temporarily unavailable.

Safety of an IV Formulation of Carbamazepine

An intravenous formulation of carbamazepine (CBZ) was administered to 113 (60 male; 53 female) persons with epilepsy aged 19-87 years. Subjects received 100mg of study drug as replacement for 100mg of their usual morning dose of CBZ. There were no significant changes in blood pressure or heart rate suggesting that this formulation can be developed as replacement therapy for persons unable to take oral CBZ.

Variability of carbamazepine and valproate concentrations in elderly nursing home residents

PURPOSE Measuring antiepileptic drug (AED) concentrations is common practice in nursing homes. Phenytoin (PHT) concentrations fluctuate substantially in many nursing home residents under constant dose conditions; however, the stability of other AED concentrations has not been studied. We investigated the variability of carbamazepine (CBZ) and valproate (VPA) concentrations under constant dose conditions in US nursing home residents. METHODS A database of elderly persons (≥65 years) in 119 nursing homes throughout the US was reviewed for residents with at least one measurement of total PHT, CBZ or VPA. Inclusion criteria for this study were three or more serum concentration measurements while on the same dose of CBZ or VPA, a two-month minimum stay, and no interfering co-medications (inducers or inhibitors). Enrollment occurred over a 2-year period. Data were collected on residents for a minimum of 6 months. KEY FINDINGS Of the 593 residents identified, 245 had CBZ or VPA concentrations measured and 44 (18%) met inclusion criteria (22 on CBZ and 22 VPA). Some subjects had little variability in AED concentrations, others had large fluctuations. Total CBZ concentrations within individuals varied as little as 0mg/L to as much as 6.3mg/L and total VPA concentrations as little as 10.0mg/L to as much as 77.6mg/L. SIGNIFICANCE The variability of PHT, CBZ, and VPA concentrations in many but not all nursing home residents implies that a re-evaluation of the role of AED concentration measurements in the management of patients is needed. Strategies for use and interpretation of AED concentration measurements need to be reevaluated.

Carbamazepine dose–concentration relationship in elderly nursing home residents

PURPOSE To describe the dose-concentration relationships of carbamazepine (CBZ) in elderly nursing home residents and the effect of sex, age, and type of co-medications. RESULTS This is a cross-sectional study of elderly (> or = 65 years) nursing home residents across the United States (N=92). Data collection was from 1 June 1998 to 31 December 2000. The mean CBZ dose was 9.2+/-5.4 mg/(kg day(-1)) (+/-Standard Deviation) and serum concentration was 5.9+/-2.2mg/L. The daily dose was significantly lower in the oldest-old age group (> or = 85 years, mean 476.9 mg/day (95% confidence interval CI) 326.5-627.3) as compared to the dose in the young-old (65-74 years, mean 724.4 mg/day (CI) 603.4-845.4) (p=0.016). Adjusted for body weight, doses were similar on a mg/(kg day(-1)) basis. The majority of observed CBZ serum concentrations were at the lower end (67.4%) or below (20.7%) the suggested therapeutic range for younger adult outpatients. CONCLUSIONS Total daily CBZ doses and patient weight decreased with age. The average dose for elderly nursing home residents was approximately 9 mg/(kg day(-1)). Carbamazepine serum concentrations were lower than those used for younger adults, suggesting that these patients may be more sensitive to CBZ.

Safety of an intravenous formulation of lamotrigine

PURPOSE Intravenous (IV) formulations are useful when treating patients where oral administration is not possible and to study certain pharmacokinetic parameters such as bioavailability. We developed a stable-labeled IV formulation of lamotrigine (LTG) for studying pharmacokinetics in epilepsy patients. METHODS Stable-labeled IV LTG was given to 20 persons with epilepsy (6 men; 14 women) with a mean age of 34.8 years (SD 11.7). A 50mg dose of LTG (stable labeled) was given intravenously and replaced 50mg of the regular morning oral dose of LTG (unlabeled, commercially available formulation). RESULTS No significant changes in blood pressure, heart rate, or adverse events including rash were attributed to administration of a 50-mg dose of the intravenous LTG formulation. CONCLUSION Our results show that LTG base that is complexed with 2-hydroxypropyl-β-cyclodextrin and stable-labeled can be given safely as a tracer replacement dose.