J. Heyward Hull

Influence of range of renal function and liver disease on predictability of creatinine clearance

Several formulas for predicting creatinine clearance (Ccr) are used for adjusting drug dosages but limited data are available on their accuracy in patients with significant renal impairment or concurrent disease. We measured 144 Ccr in 103 patients and compared results using four separate predictive methods. Of nine common diseases in these patients, liver disease was associated with a large (p < 0.02) prediction error (overprediction). After data from eight patients with liver disease were removed, there was good overall correlation between predicted and measured Ccr (r2 = 0.91 for each method) but only two of the methods (I and IV) were consistently accurate in all ranges of renal function. Methods for predicting Ccr should not be used in patients with liver disease.

Codeine disposition in smokers and nonsmokers

The bioavailability of codeine and extent of its transformation to morphine were studied in 12 smoking and 11 nonsmoking subjects after single doses of 60 mg IM codeine and 60 mg codeine sulfate orally, given 1 wk apart. Codeine and morphine plasma concentrations over the 12‐hr period after drug were determined by radioimmunoassay (RIA). No differences were found between smokers and nonsmokers with respect to maximum plasma concentration (Cmax) of codeine, time to attain this concentration (tmax), codeine plasma half‐life (t½), or areas under plasma concentration‐time curves (AUC) for codeine or morphine. There was a faster, but clinically unimportant, mean apparent plasma clearance in smokers (52.8 ± 2.3 (SEM) ml/min/70 kg) than in nonsmokers (45.0 ±2.1 ml/min/70 kg) after intramuscular injection only. Mean oral codeine bioavailability in smokers (54.8 ± 4.9%) and in nonsmokers (50.2 ± 2.1%) did not differ. Plasma morphine AUC values were higher after oral doses than after intramuscular injections, suggesting a first‐pass O‐demethylation of codeine. For six of these subjects plasma morphine AUC values were very low after both routes of administration, suggesting less O‐demethylation of codeine in these than in the remaining 17 subjects. The observation of higher morphine AUC values after oral codeine, coupled with clinical reports of greater analgesic potency with intramuscular codeine, does not support the hypothesis that the analgesic properties of this drug are mediated entirely by biotransformation to morphine.

The Influence of Sex, Ethnicity, and CYP2B6 Genotype on Bupropion Metabolism as an Index of Hepatic CYP2B6 Activity in Humans

The effects of sex, ethnicity, and genetic polymorphism on hepatic CYP2B6 (cytochrome P450 2B6) expression and activity were previously demonstrated in vitro. Race/ethnic differences in CYP2B6 genotype and phenotype were observed only in women. To identify important covariates associated with interindividual variation in CYP2B6 activity in vivo, we evaluated these effects in healthy volunteers using bupropion (Wellbutrin SR GlaxoSmithKline, Research Triangle Park, NC) as a CYP2B6 probe substrate. A fixed 150-mg oral sustained-release dose of bupropion was administered to 100 healthy volunteers comprising four sex/ethnicity cohorts (n = 25 each): Caucasian men and Caucasian, African American, and Hispanic women. Blood samples were obtained at 0 and 6 hours postdose for the measurement of serum bupropion (BU) and hydroxybupropion (HB) concentrations. Whole blood was obtained at baseline for CYP2B6 genotyping. To characterize the relationship between CYP2B6 activity and ethnicity, sex, and genotype when accounting for serum BU concentrations (dose-adjusted log10-transformed), analysis of covariance model was fitted in which the dependent variable was CYP2B6 activity represented as the log10-transformed, metabolic ratio of HB to BU concentrations. Several CYP2B6 polymorphisms were associated with CYP2B6 activity. Evidence of dependence of CYP2B6 activity on ethnicity or genotype-by-ethnicity interactions was not detected in women. These results suggest that CYP2B6 genotype is the most important patient variable for predicting the level of CYP2B6 activity in women, when measured by the metabolism of bupropion. The bupropion metabolic ratio appears to detect known differences in CYP2B6 activity associated with genetic polymorphism, across different ethnic groups. Prospective studies will be needed to validate the use of bupropion as a probe substrate for clinical use.

Pilot study of rosiglitazone as an in vivo probe of paclitaxel exposure.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Paclitaxel and rosiglitazone are primarily metabolized by CYP2C8 and their in vitro metabolism by human liver microsomes is correlated. Probe assays that quantify the in vivo activity of CYP enzymes which are important in drug metabolism have been developed for use in clinical pharmacology research. A probe of CYP2C8 that is easy to administer and interpret may be valuable for individualized dosing of paclitaxel. WHAT THIS STUDY ADDS • This pilot study demonstrates for the first time that there is an in vivo correlation between paclitaxel and rosiglitazone exposure. The finding, that a single rosiglitazone plasma concentration after oral dosing may explain significant variance in paclitaxel exposure, suggests that rosiglitazone may satisfy the requirements of a clinically useful in vivo probe. However, it is acknowledged that there is a need for further studies evaluating the use of rosiglitazone as a CYP2C8 probe and quantifying the relationship, in order to guide dosing of narrow therapeutic index drugs metabolized primarily by CYP2C8, such as paclitaxel. AIMS To evaluate the use of rosiglitazone and the erythromycin breath test (ERMBT), as probes of CYP2C8 and CYP3A4, respectively, to explain inter-individual variability in paclitaxel exposure. METHODS The concentration of rosiglitazone at 3 h and ERMBT results were included in a regression model to explain the variability in paclitaxel exposure in 14 subjects. RESULTS Rosiglitazone concentration was significantly correlated with paclitaxel exposure (P= 0.018) while ERMBT had no predictive value (P= 0.47). CONCLUSIONS The correlation between the exposure of rosiglitazone and paclitaxel likely reflects mutual dependence on the activity of CYP2C8. Rosiglitazone or similar agents may have value as in vivo probes of CYP2C8 activity.

Impact of Video Technology on Efficiency of Pharmacist-Provided Anticoagulation Counseling and Patient Comprehension

Background: Discharge anticoagulation counseling is important for ensuring patient comprehension and optimizing clinical outcomes. As pharmacy resources become increasingly limited, the impact of informational videos on the counseling process becomes more relevant. Objective: To evaluate differences in pharmacist time spent counseling and patient comprehension (measured by the Oral Anticoagulation Knowledge [OAK] test) between informational videos and traditional face-to-face (oral) counseling. Methods: This prospective, open, parallel-group study at an academic medical center randomized 40 individuals—17 warfarin-naïve (“New Start”) and 23 with prior warfarin use (“Restart”)—to receive warfarin discharge education by video or face-to-face counseling. “Teach-back” questions were used in both groups. Results: Although overall pharmacist time was reduced in the video counseling group (P < 0.001), an interaction between prior warfarin use and counseling method (P = 0.012) suggests the difference between counseling methods was smaller in New Start participants. Following adjustment, mean total time was reduced 8.71 (95% CI = 5.15-12.26) minutes (adjusted P < 0.001) in Restart participants and 2.31 (−2.19 to 6.81) minutes (adjusted P = 0.472) in New Start participants receiving video counseling. Postcounseling OAK test scores did not differ. Age, gender, socioeconomic status, and years of education were not predictive of total time or OAK test score. Conclusion: Use of informational videos coupled with teach-back questions significantly reduced pharmacist time spent on anticoagulation counseling without compromising short-term patient comprehension, primarily in patients with prior warfarin use. Study results demonstrate that video technology provides an efficient method of anticoagulation counseling while achieving similar comprehension.

Assessment of a Candidate Marker Constituent Predictive of a Dietary Substance–Drug Interaction: Case Study with Grapefruit Juice and CYP3A4 Drug Substrates

Dietary substances, including herbal products and citrus juices, can perpetrate interactions with conventional medications. Regulatory guidances for dietary substance–drug interaction assessment are lacking. This deficiency is due in part to challenges unique to dietary substances, a lack of requisite human-derived data, and limited jurisdiction. An in vitro–in vivo extrapolation (IVIVE) approach to help address some of these hurdles was evaluated using the exemplar dietary substance grapefruit juice (GFJ), the candidate marker constituent 6′,7′-dihydroxybergamottin (DHB), and the purported victim drug loperamide. First, the GFJ-loperamide interaction was assessed in 16 healthy volunteers. Loperamide (16 mg) was administered with 240 ml of water or GFJ; plasma was collected from 0 to 72 hours. Relative to water, GFJ increased the geometric mean loperamide area under the plasma concentration–time curve (AUC) significantly (1.7-fold). Second, the mechanism-based inhibition kinetics for DHB were recovered using human intestinal microsomes and the index CYP3A4 reaction, loperamide N-desmethylation (KI [concentration needed to achieve one-half kinact], 5.0 ± 0.9 µM; kinact [maximum inactivation rate constant], 0.38 ± 0.02 minute−1). These parameters were incorporated into a mechanistic static model, which predicted a 1.6-fold increase in loperamide AUC. Third, the successful IVIVE prompted further application to 15 previously reported GFJ-drug interaction studies selected according to predefined criteria. Twelve of the interactions were predicted to within the 25% predefined criterion. Results suggest that DHB could be used to predict the CYP3A4-mediated effect of GFJ. This time- and cost-effective IVIVE approach could be applied to other dietary substance–drug interactions to help prioritize new and existing drugs for more advanced (dynamic) modeling and simulation and clinical assessment.

Absorption of Digoxin from Tablets and Capsules in Subjects with Malabsorption Syndromes

The relative steady-state bioavailability of two oral digoxin dosage forms was studied in 17 subjects with malabsorption syndromes. Male subjects received the following treatments in randomized crossover fashion for 14 days: Three 0.125-mg digoxin tablets or three 0.1-mg digoxin capsules once daily. Female subjects received digoxin on the same schedule but at two-thirds the dose. Serum and urine samples were collected and analyzed for digoxin by radioimmunoassay, and treatments were compared by evaluating pharmacokinetic parameters. The mean area under the serum concentration versus time curve for tablets (28.1 h•nmol/L [21.9 h•ng/mL]) was smaller (p < 0.03) than that for capsules (31.1 h•nmol/L [24.3 h•ng/mL]), and the mean maximum serum digoxin concentration for tablets (2.9 nmol/L [2.3 ng/mL]) was lower (p < 0.02) than that for capsules (4.0 nmol/L [3.1 ng/mL]). There was no difference in cumulative urinary excretion of digoxin between the two treatments. In contrast to previous reports, we observed that digoxin from Lanoxin Tablets appears to be well absorbed in subjects with malabsorption. Nevertheless, these subjects absorbed digoxin from capsules better than from tablets, with the greatest differences occurring in subjects without a colon and in those subjects with the lowest serum carotene concentrations.The relative steady-state bioavailability of two oral digoxin dosage forms was studied in 17 subjects with malabsorption syndromes. Male subjects received the following treatments in randomized crossover fashion for 14 days: Three 0.125-mg digoxin tablets or three 0.1-mg digoxin capsules once daily. Female subjects received digoxin on the same schedule but at two-thirds the dose. Serum and urine samples were collected and analyzed for digoxin by radioimmunoassay, and treatments were compared by evaluating pharmacokinetic parameters. The mean area under the serum concentration versus time curve for tablets (28.1 h•nmol/L [21.9 h•ng/mL]) was smaller (p < 0.03) than that for capsules (31.1 h•nmol/L [24.3 h•ng/mL]), and the mean maximum serum digoxin concentration for tablets (2.9 nmol/L [2.3 ng/mL]) was lower (p < 0.02) than that for capsules (4.0 nmol/L [3.1 ng/mL]). There was no difference in cumulative urinary excretion of digoxin between the two treatments. In contrast to previous reports, we observed th...

A pocket calculator program for pharmacokinetic dosing of drugs exhibiting single compartment first-order elimination and zero-order or first-order absorption

A pocket computer program has been designed to assist clinicians in the appropriate administration of most drugs exhibiting single compartment first-order elimination and either zero-order (intravenous infusions) or first-order (intramuscular and oral) absorption. The program utilizes well-established pharmacokinetic parameters to calculate an optimal drug dose and dosing interval based upon a patients demographic characteristics and the drug half-life, volume of distribution, and absorption rate constant or infusion time. It also allows the user to estimate peak and trough drug serum concentrations. When measured serum concentrations are available during steady state, it is possible to determine individual patient drug half-life and volume of distribution for more accurate adjustments in dose and/or dosing interval. Usage of this program should enable clinicians to better select effective but safe drug dosing regimens based on individual patient needs and characteristics.