ELQ-331 as a prototype for extremely durable chemoprotection against malaria.

BACKGROUND: The potential benefits of long-acting injectable chemoprotection (LAI-C) against malaria have been recently recognized, prompting a call for suitable candidate drugs to help meet this need. On the basis of its known pharmacodynamic and pharmacokinetic profiles after oral dosing, ELQ-331, a prodrug of the parasite mitochondrial electron transport inhibitor ELQ-300, was selected for study of pharmacokinetics and efficacy as LAI-C in mice. METHODS: Four trials were conducted in which mice were injected with a single intramuscular dose of ELQ-331 or other ELQ-300 prodrugs in sesame oil with 1.2% benzyl alcohol; the ELQ-300 content of the doses ranged from 2.5 to 30 mg/kg. Initial blood stage challenges with Plasmodium yoelii were used to establish the model, but the definitive study measure of efficacy was outcome after sporozoite challenge with a luciferase-expressing P. yoelii, assessed by whole-body live animal imaging. Snapshot determinations of plasma ELQ-300 concentration ([ELQ-300]) were made after all prodrug injections; after the highest dose of ELQ-331 (equivalent to 30 mg/kg ELQ-300), both [ELQ-331] and [ELQ-300] were measured at a series of timepoints from 6 h to 5½ months after injection. RESULTS: A single intramuscular injection of ELQ-331 outperformed four other ELQ-300 prodrugs and, at a dose equivalent to 30 mg/kg ELQ-300, protected mice against challenge with P. yoelii sporozoites for at least 4½ months. Pharmacokinetic evaluation revealed rapid and essentially complete conversion of ELQ-331 to ELQ-300, a rapidly achieved (< 6 h) and sustained (4-5 months) effective plasma ELQ-300 concentration, maximum ELQ-300 concentrations far below the estimated threshold for toxicity, and a distinctive ELQ-300 concentration versus time profile. Pharmacokinetic modeling indicates a high-capacity, slow-exchange tissue compartment which serves to accumulate and then slowly redistribute ELQ-300 into blood, and this property facilitates an extremely long period during which ELQ-300 concentration is sustained above a minimum fully-protective threshold (60-80 nM). CONCLUSIONS: Extrapolation of these results to humans predicts that ELQ-331 should be capable of meeting and far-exceeding currently published duration-of-effect goals for anti-malarial LAI-C. Furthermore, the distinctive pharmacokinetic profile of ELQ-300 after treatment with ELQ-331 may facilitate durable protection and enable protection for far longer than 3 months. These findings suggest that ELQ-331 warrants consideration as a leading prototype for LAI-C.

A phase II study of sulforaphane-rich broccoli sprout extracts in men with recurrent prostate cancer.

INTRODUCTION: Diets high in cruciferous vegetables are associated with lower risk of incidence of prostate cancer, including aggressive forms of this disease. Human intervention studies with cruciferous vegetable-rich diets also demonstrate modulation of gene expression in important pathways in prostate cells. PURPOSE: Sulforaphane is a constituent of these foods postulated to harbor the anti-neoplastic activity based on multiple tumor models. Our own work demonstrates that sulforaphane inhibits AR signaling in prostate cancer cells. Here, we report results from the first clinical trial of sulforaphane-rich extracts in men with prostate cancer. METHODS: We treated 20 patients who had recurrent prostate cancer with 200 µmoles/day of sulforaphane-rich extracts for a maximum period of 20 weeks and determined the proportion of patients with ≥50% PSA declines, the primary endpoint. Only one subject experienced a ≥50% PSA decline. Thus, the primary endpoint was not achieved. Seven patients experienced smaller PSA declines (<50%). There was also a significant lengthening of the on-treatment PSA doubling time (PSADT) compared with the pre-treatment PSADT [6.1 months pre-treatment vs. 9.6 months on-treatment (p = 0.044)]. Finally, treatment with sulforaphane-rich extracts was safe with no Grade 3 adverse events. CONCLUSIONS: Treatment with 200 µmoles/day of sulforaphane-rich extracts did not lead to ≥50% PSA declines in the majority of patients. However, because of the safety of treatment and the effects on PSADT modulation, further studies, including those with higher doses, may be warranted to clarify the role of sulforaphane as a prevention agent or treatment agent.

Effect of the ethinylestradiol/levonorgestrel combined oral contraceptive on the activity of cytochrome P4503A in obese women.

AIM(S): While it is known that CYP3A4/5 activity is decreased with combined oral contraceptive (COC) use and obesity suppresses CYP expression, the combined effects of obesity and COC use on CYP3A4/5 activity are unclear. Therefore, our aim was to examine the effect of COC usage on CYP3A4/5 activity in obese women. METHODS: Thirty-four, obese (body mass index, BMI > 30 kg m(-2)) women of reproductive age (18-35 years old) were placed on a COC pill containing 20 µg ethinylestradiol/100 µg levonorgestrel for 21 days starting at the onset of menses. A midazolam pharmacokinetic study was conducted prior to initiation and after 21 days of COC treatment. Serial blood samples were collected and plasma concentrations of midazolam were measured using liquid chromatography tandem mass spectrometry. Pharmacokinetic parameters were estimated using a non-compartmental method. RESULTS: Midazolam clearance, a surrogate measure of CYP3A4/5 activity, was significantly decreased upon COC use (63.3 l h(-1) vs. 53.9 l h(-1), P < 0.05). A median decrease of 5.6 l h(-1) (95% CI -4.1, 13.3 l h(-1)) was observed. However, the magnitude of change was similar to that reported in women with normal BMI. CONCLUSIONS: Although we hypothesized that obesity might amplify the impact on CYP3A4/5 activity in COC users, we found that this was not the case. This finding is reassuring regarding potential additional drug-drug interactions in obese COC users as CYP3A4/5 is a major enzyme in the metabolism of many marketed drugs.

Pharmacokinetic study of lipoic acid in multiple sclerosis: comparing mice and human pharmacokinetic parameters.

Lipoic acid is a natural antioxidant available as an oral supplement from a number of different manufacturers. Lipoic acid administered subcutaneously is an effective therapy for murine experimental autoimmune encephalomyelitis, a model of multiple sclerosis. The aim of this study was to compare serum lipoic acid levels with oral dosing in patients with multiple sclerosis with serum levels in mice receiving subcutaneous doses of lipoic acid. We performed serum pharmacokinetic studies in patients with multiple sclerosis after a single oral dose of 1200 mg lipoic acid. Patients received one of the three different racemic formulations randomly: tablet (Formulation A) and capsules (Formulations B and C). Mice pharmacokinetic studies were performed with three different subcutaneous doses (20, 50 and 100 mg/kg racemic lipoic acid). The pharmacokinetic parameters included Maximum Serum Concentrations (C(max) in microg/ml) and area under the curve (0-infinity) (AUC ( 0-infinity) in microg*min/ml). We found mean C(max) and AUC (0-infinity) in patients with multiple sclerosis as follows: group A (N = 7) 3.8 +/- 2.6 and 443.1 +/- 283.9; group B (N = 8) 9.9 +/- 4.5 and 745.2 +/- 308.7 and group C (N = 8) 10.3 +/- 3.8 and 848.8 +/- 360.5, respectively. Mean C(max) and AUC (0-infinity) in the mice were: 100 mg/kg lipoic acid: 30.9 +/- 2.9 and 998 +/- 245; 50 mg/kg lipoic acid: 7.6 +/- 1.4 and 223 +/- 20; 20 mg/kg lipoic acid: 2.7 +/- 0.7 and 119 +/- 33. We conclude that patients taking 1200 mg of lipoic acid from two of the three oral formulations achieved serum C(max) and AUC levels comparable to that observed in mice receiving 50 mg/kg subcutaneous dose of lipoic acid, which is a highly therapeutic dose in experimental autoimmune encephalomyelitis. A dose of 1200 mg oral lipoic acid can achieve therapeutic serum levels in patients with multiple sclerosis.

Blood-based biomarkers for prediction of intracranial hemorrhage and outcome in patients with moderate or severe traumatic brain injury.

BACKGROUND: Early identification of traumatic intracranial hemorrhage (ICH) has implications for triage and intervention. Blood-based biomarkers were recently approved by the Food and Drug Administration (FDA) for prediction of ICH in patients with mild traumatic brain injury (TBI). We sought to determine if biomarkers measured early after injury improve prediction of mortality and clinical/radiologic outcomes compared with Glasgow Coma Scale (GCS) alone in patients with moderate or severe TBI (MS-TBI). METHODS: We measured glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein-2 (MAP-2) on arrival to the emergency department (ED) in patients with blunt TBI enrolled in the placebo arm of the Prehospital TXA for TBI Trial (prehospital GCS score, 3-12; SPB, > 90). Biomarkers were modeled individually and together with prehospital predictor variables [PH] (GCS score, age, sex). Data were divided into a training data set and test data set for model derivation and evaluation. Models were evaluated for prediction of ICH, mass lesion, 48-hour and 28-day mortality, and 6-month Glasgow Outcome Scale-Extended (GOS-E) and Disability Rating Scale (DRS). Area under the curve (AUC) was evaluated in test data for PH alone, PH + individual biomarkers, and PH + three biomarkers. RESULTS: Of 243 patients with baseline samples (obtained a median of 84 minutes after injury), prehospital GCS score was 8 (interquartile range, 5-10), 55% had ICH, and 48-hour and 28-day mortality were 7% and 13%, respectively. Poor neurologic outcome at 6 months was observed in 34% based on GOS-E of 4 or less, and 24% based on DRS greater than or equal to7. Addition of each biomarker to PH improved AUC in the majority of predictive models. GFAP+PH compared with PH alone significantly improved AUC in all models (ICH, 0.82 vs. 0.64; 48-hour mortality, 0.84 vs. 0.71; 28-day mortality, 0.84 vs. 0.66; GOS-E, 0.78 vs. 0.69; DRS, 0.84 vs. 0.81, all p < 0.001). CONCLUSION: Circulating blood-based biomarkers may improve prediction of neurological outcomes and mortality in patients with MS-TBI over prehospital characteristics alone. Glial fibrillary acidic protein appears to be the most promising. Future evaluation in the prehospital setting is warranted. LEVEL OF EVIDENCE: Prospective, Prognostic and Epidemiological, level II.

Daptomycin pharmacokinetics in adult oncology patients with neutropenic fever.

Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant Staphylococcus aureus. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means +/- standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (C(max)) was 49.04 +/- 12.42 microg/ml (range, 21.54 to 75.20 microg/ml), the 24-h plasma concentration was 6.48 +/- 5.31 microg/ml (range, 1.48 to 29.26 microg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 +/- 523.53 microg.h/ml (range, 164.64 to 3155.11 microg.h/ml), the volume of distribution at steady state was 0.18 +/- 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 +/- 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 +/- 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 +/- 20.66 h (range, 7.00 to 121.73 h), and the median time to C(max) was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 +/- 0.02. All patients achieved C(max)/MIC and AUC from time zero to 24 h (AUC(0-24))/MIC ratios for a bacteriostatic effect against Streptococcus pneumoniae. Twenty-seven patients (93%) achieved a C(max)/MIC ratio for a bacteriostatic effect against S. aureus, and 28 patients (97%) achieved an AUC(0-24)/MIC ratio for a bacteriostatic effect against S. aureus. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for S. pneumoniae and 90% of patients for S. aureus. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.

Effect of pregnancy on the pharmacokinetics of paclitaxel: a case report.

Breast cancer during pregnancy is increasingly common as women delay childbearing until later in life. Safe administration of adjuvant chemotherapy during pregnancy has been reported. Physiologic and metabolic changes during pregnancy could alter the pharmacokinetics of these agents. This is a pilot study to prospectively study the pharmacokinetics of chemotherapeutic agents during pregnancy. Herein, we report the initial results with paclitaxel in the first patient.

Correcting oral contraceptive pharmacokinetic alterations due to obesity: a randomized controlled trial.

OBJECTIVE: To determine if increasing the hormone dose or eliminating the hormone-free interval improves key pharmacokinetic (PK) alterations caused by obesity during oral contraceptive (OC) use. STUDY DESIGN: Obese [body mass index (BMI)≥30 kg/m(2)], ovulatory, otherwise healthy, women received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) dosed cyclically (21 days active pills with 7-day placebo week) for two cycles and then were randomized for two additional cycles to the following: continuous cycling (CC, a dose neutral arm using the same OC with no hormone-free interval) or increased dose (ID, a dose escalation arm using an OC containing 30 mcg EE/150 mcg LNG cyclically). During Cycles 2, 3 and 4, outpatient visits were performed to assess maximum serum concentration (Cmax), area under the curve (AUC0-∞) and time to steady state as well as pharmacodynamics. These key PK parameters were calculated and compared within groups between baseline and treatment cycles. RESULTS: A total of 31 women enrolled and completed the study (CC group, n=16; ID group, n=15). Demographics were similar between groups [mean BMI: CC, 38 kg/m(2) (S.D. 5.1); ID, 41 kg/m(2) (S.D. 7.6)]. At baseline, the key LNG PK parameters were no different between groups; average time to reach steady state was 12 days in both groups; Cmax were CC: 3.82±1.28 ng/mL and ID: 3.13±0.87 ng/mL; and AUC0-∞ were CC: 267±115 h ng/mL and ID: 199±75 h ng/mL. Following randomization, the CC group maintained steady-state serum levels whereas the ID group had a significantly higher Cmax (p<.001) but again required 12 days to achieve steady state. However, AUC was not significantly different between CC (412±255 h ng/mL) and ID (283±130 h ng/mL). Forty-five percent (14/31) of the study population had evidence of an active follicle-like structure prior to randomization and afterwards this decreased to 9% (3/31). CONCLUSION: Both increasing the OC dose and continuous dosing appear to counteract the impact of obesity on key OC PK parameters. IMPLICATIONS: Obesity adversely affects the pharmacokinetics of very low dose OC pills. Although the impact of these changes on OC efficacy is still under debate, PK parameters can be normalized in obese users by continuous dosing or increasing to a low-dose pill.

Are children undergoing cardiac surgery receiving antibiotics at subtherapeutic levels?

OBJECTIVES: Perioperative antibiotics have decreased-but not eradicated-postoperative infections. In patients undergoing cardiac surgery with cardiopulmonary bypass, the dilutional effect of the priming and any additional volume given during the procedure may lead to subtherapeutic antibiotic levels. Our aim was to determine if children undergoing cardiac surgery with cardiopulmonary bypass receive perioperative antibiotics at subtherapeutic levels. METHODS: Using published pharmacokinetic data on cefuroxime, we developed a computer simulation model to generate a nomogram predicting patients at risk for subtherapeutic cefuroxime levels based on time from initial dosing and additional volume given. RESULTS: A computer-generated 1-compartment pharmacokinetic model was created to predict cefuroxime plasma levels over time for patients of all weights and additional volumes given for both a 25- and 50-mg/kg intravenous dose. For example, following a 25-mg/kg dose, a patient receiving an additional volume of 275 mL/kg is predicted to be subtherapeutic (<16 mg/L=4×minimum inhibitory concentration) at 4 hours. Our nomogram predicts all patients will be subtherapeutic at 8 hours, consistent with general pediatrics dosing schemes. Following a 50-mg/kg dose, levels are predicted to be subtherapeutic after an additional volume of 315 mL/kg at 5.5 hours. CONCLUSIONS: Our model predicts which patients undergoing cardiac surgery with cardiopulmonary will have subtherapeutic cefuroxime levels. This nomogram enables providers to determine when to administer additional antibiotics in patients receiving large additional volumes during cardiac surgeries. This rational approach to perioperative antibiotic dosing may result in a reduction in postoperative infection in this vulnerable patient population.

Analysis of tacrolimus and creatinine from a single dried blood spot using liquid chromatography tandem mass spectrometry.

Long term therapeutic drug monitoring and assessment of renal function are required in renal transplant recipients on immunosuppressant therapy such as tacrolimus. Dry blood spots (DBS) have been used successfully in the clinic for many years and offers a convenient, simple and non-invasive method for repeated blood tests. We developed and performed a preliminary validation of a method for the analysis of tacrolimus and creatinine from a single DBS using liquid chromatography-tandem mass spectrometric (LC-MS/MS). Tacrolimus and creatinine were extracted from a 6mm punch with a mixture of methanol/acetonitrile containing ascomycin and deuterated creatinine as internal standards. A 10 µl aliquot of the extract was analyzed directly after dilution for creatinine with normal phase high performance liquid chromatography and multiple reaction monitoring. The remainder of the extract was processed and analyzed for tacrolimus. The lower limit of quantification for tacrolimus was 1 ng/ml with accuracy of 0.34% bias and precision (CV) of 11.1%. The precision ranged from 1.33% to 7.68% and accuracy from -4.44% to 11.6% bias for the intra- and inter-day analysis. The lower limit of quantification of creatinine was 0.01 mg/dL with precision of 7.94%. Accuracy was based on recovery of additional creatinine spiked into whole blood samples and ranged from -2.45% bias at 5 mg/dL to 3.75% bias at 0.5 mg/dL. Intra- and inter-day precision was from 3.48 to 4.11%. The assay was further validated with DBS prepared from pediatric renal transplant recipients. There was excellent correlation between the levels of tacrolimus and creatinine obtained from the clinical laboratory and the DBS method developed. After additional validation, this assay may have a significant impact on compliance with medication intake as well as potentially lowering the cost associated with intravenous blood draws in clinical laboratories.

Prolonged monitoring of ethinyl estradiol and levonorgestrel levels confirms an altered pharmacokinetic profile in obese oral contraceptives users.

BACKGROUND: Pharmacokinetic (PK) parameters based on short sampling times (48 h or less) may contain inaccuracies due to their dependency on extrapolated values. This study was designed to measure PK parameters with greater accuracy in obese users of a low-dose oral contraceptive (OC) and to correlate drug levels with assessments of end-organ activity. STUDY DESIGN: Obese [body mass index (BMI) ≥30 kg/m2], ovulatory, otherwise healthy women (n=32) received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) for two cycles. EE and LNG PK parameters were characterized for 168 h at the end of Cycle 1. During cycle 2, biweekly outpatient visits were performed to assess cervical mucus, monitor ovarian activity with transvaginal ultrasound and obtain serum samples to measure EE, LNG, estradiol and progesterone levels. PK parameters were calculated and correlated with end-organ activity and compared against control samples obtained from normal and obese women sampled up to 48 h in a previous study. Standard determination of PK accuracy was performed, defined by the dependency on extrapolated values ('excess' area under the curve of 25% or less). RESULTS: The mean BMI was 39.4 kg/m2 (SD 6.6) with a range of 30-64 kg/m2. Key LNG PK parameters were as follows: clearance, 0.52 L/h (SD 0.24); half-life, 65 h (SD 40); area under the curve (AUC), 232 h*ng/mL (SD 102); and time to reach steady state, 13.6 days (SD 8.4). The majority of subjects had increased ovarian activity with diameter of follicles ≥8 mm (n=25), but only seven women had follicles ≥10 mm plus cervical mucus scores ≥5. Evidence of poor end-organ suppression did not correlate with the severity of the alterations in PK. As compared to historical normal and obese controls (48-h PK sampling), clearance, half-life, AUC and time to reach steady state were found to be significantly different (p≤.05) in obese women undergoing a longer duration of PK sampling (168 h). Longer sampling also improved PK accuracy for obese women (excess AUC 20%) as compared to both normal and obese controls undergoing shorter sampling times (48 h) with excess AUCs of 25% and 50%, respectively. CONCLUSIONS: Obesity results in significant alterations in OC steroid PK parameters, but the severity of these alterations did not correlate with end-organ suppression. A longer PK sampling interval (168 h vs. 48 h) improved the accuracy of PK testing.

Aprepitant pharmacokinetics and assessing the impact of aprepitant on cyclophosphamide metabolism in cancer patients undergoing hematopoietic stem cell transplantation.

Aprepitant, a neurokinin antagonist, is an effective antiemetic agent in chemotherapy for delayed nausea and vomiting. The study objective was to evaluate the pharmacokinetics of aprepitant and concurrent cyclophosphamide (CY), often a component of hematopoietic stem cell transplant (HSCT) conditioning regimen, in cancer patients undergoing HSCT. Forty subjects were randomized to either aprepitant or placebo in addition to standard antiemetics. Aprepitant or placebo was started 1 hour before the first chemotherapy or radiation dose for HSCT conditioning and administered daily until 4 days after infusion of the hematopoietic cell graft (for a total of 10-12 days). Serial blood samples were collected for aprepitant and CY plus 2 important CY metabolites. The results indicate that aprepitant is well absorbed and does not auto-induce its metabolism. No significant drug interaction was observed with CY or its metabolites. A significant portion of the patients had subtherapeutic aprepitant concentrations; however, chemotherapy-induced nausea and vomiting were effectively managed. No dosage adjustment was necessary, and administration of aprepitant in HSCT at the prescribed dosage of 125 mg orally on day 1 and 80 mg orally on each consecutive day through day +4 after HSCT was well tolerated with no significant changes in CY pharmacokinetic parameters.

Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity.

BACKGROUND: This study was conducted to determine whether increased body mass index (BMI) affects oral contraceptive (OC) pharmacokinetics and suppression of hypothalamic-pituitary-ovarian (HPO) axis activity. STUDY DESIGN: Ovulatory reproductive-age women with normal weight (BMI <25 kg/m(2); n=10) and with obesity (BMI >30 kg/m(2); n=10) received OCs for two cycles (prospective cohort). Subjects were admitted for two 48-h inpatient stays at the beginning and end of the hormone-free interval. Ethinyl estradiol and levonorgestrel (LNG) levels were evaluated during both inpatient stays. Gonadotropin pulsatility (follicle-stimulating hormone and luteinizing hormone) was measured during the second inpatient stay. Estradiol (E(2)) and progesterone (P) were measured daily during inpatient stays and twice per week in Cycle 2. RESULTS: BMI was greater in the obese compared to the normal-BMI group [37.3 kg/m(2) (SD, 6.0) vs. 21.9 kg/m(2) (SD, 1.6); p<.05]. The LNG half-life was significantly longer in the obese group (52.1+/-29.4 vs. 25.6+/-9.3 h, p<.05), which correlated with a lower maximum LNG concentration on Cycle 2, Day 1 [1.9 ng/mL (SD, 0.5) vs. 2.5 ng/mL (SD, 0.7)] and a longer time to reach steady state (10 vs. 5 days) in obese women. There were no significant differences in volume of distribution between groups. LH pulse parameters did not differ statistically between groups but trended toward greater HPO activity in the obese group. Additionally, more obese (6/10 vs. 3/10 normal BMI, p>.05) women exhibited E(2) levels consistent with development of a dominant follicle and P levels consistent with ovulation (2/10 vs. 1/10) during Cycle 2. CONCLUSIONS: Compared to women with normal BMI, obese women exhibit differences in OC pharmacokinetics that are associated with greater HPO activity.

Drug dosing adjustments in patients with chronic kidney disease.

Chronic kidney disease affects renal drug elimination and other pharmacokinetic processes involved in drug disposition (e.g., absorption, drug distribution, nonrenal clearance [metabolism]). Drug dosing errors are common in patients with renal impairment and can cause adverse effects and poor outcomes. Dosages of drugs cleared renally should be adjusted according to creatinine clearance or glomerular filtration rate and should be calculated using online or electronic calculators. Recommended methods for maintenance dosing adjustments are dose reductions, lengthening the dosing interval, or both. Physicians should be familiar with commonly used medications that require dosage adjustments. Resources are available to assist in dosing decisions for patients with chronic kidney disease.

Administration of tobramycin in the beginning of the hemodialysis session: a novel intradialytic dosing regimen.

BACKGROUND: Aminoglycoside antibiotic efficacy is related to peak concentration (C(max)) and postantibiotic effect, whereas toxicity is directly related to body exposure as measured by area under the serum concentration versus time curve (AUC). On the basis of pharmacokinetic simulation models, tobramycin administration during the first 30 min of high-flux hemodialysis achieves similar C(max) but significantly lower AUC and prehemodialysis concentrations compared with conventional dosing in the last 30 min of hemodialysis. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: To test this hypothesis, a pilot study in which five adult chronic hemodialysis patients who were undergoing high-flux dialysis received one dose of tobramycin 1.5 mg/kg intravenously during the first or last 30 min of hemodialysis was conducted. After a 1-mo washout period, patients crossed over to the other treatment schedule. Tobramycin serum concentrations were measured to determine C(max), interdialytic and intradialytic elimination rate constants and half-lives, AUC, and clearance. RESULTS: Tobramycin administration during the first and last 30 min of hemodialysis resulted in similar C(max) of 5.63 +/- 0.49 and 5.83 +/- 0.67 mg/L (P > 0.05) but significantly lower prehemodialysis concentrations of 0.16 +/- 0.09 and 2.44 +/- 0.43 mg/L (P < 0.001) and AUC of 21.06 and 179.23 +/- 25.84 mg/h per L (P < 0.001), respectively. CONCLUSIONS: Tobramycin administration during the first 30 min of hemodialysis results in similar C(max) but lower AUC to conventional dosing, which may translate into comparable efficacy but lower toxicity.

The use of wireless laptop computers for computer-assisted learning in pharmacokinetics.

OBJECTIVE: To implement computer-assisted learning workshops into pharmacokinetics courses in a doctor of pharmacy (PharmD) program. DESIGN: Workshops were designed for students to utilize computer software programs on laptop computers to build pharmacokinetic models to predict drug concentrations resulting from various dosage regimens. In addition, students were able to visualize through graphing programs how altering different parameters changed drug concentration-time curves. Surveys were conducted to measure students' attitudes toward computer technology before and after implementation. Finally, traditional examinations were used to evaluate student learning. ASSESSMENT: Doctor of pharmacy students responded favorably to the use of wireless laptop computers in problem-based pharmacokinetic workshops. Eighty-eight percent (n = 61/69) and 82% (n = 55/67) of PharmD students completed surveys before and after computer implementation, respectively. Prior to implementation, 95% of students agreed that computers would enhance learning in pharmacokinetics. After implementation, 98% of students strongly agreed (p < 0.05) that computers enhanced learning. Examination results were significantly higher after computer implementation (89% with computers vs. 84% without computers; p = 0.01). CONCLUSION: Implementation of wireless laptop computers in a pharmacokinetic course enabled students to construct their own pharmacokinetic models that could respond to changing parameters. Students had greater comprehension and were better able to interpret results and provide appropriate recommendations. Computer-assisted pharmacokinetic techniques can be powerful tools when making decisions about drug therapy.