Kazuo Yago

Population Pharmacokinetics of Arbekacin, Vancomycin, and Panipenem in Neonates

ABSTRACT Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (n = 41), vancomycin (n = 19), or panipenem (n = 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (V) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CLarbekacin = 0.0238 × BW/serum creatinine level for PCAs of <33 weeks and CLarbekacin = 0.0367 × BW/serum creatinine level for PCAs of ≥33 weeks, Varbekacin = 0.54 liters/kg, CLvancomycin = 0.0250 × BW/serum creatinine level for PCAs of <34 weeks and CLvancomycin = 0.0323 × BW/serum creatinine level for PCAs of ≥34 weeks, Vvancomycin = 0.66 liters/kg, CLpanipenem = 0.0832 for PCAs of <33 weeks and CLpanipenem = 0.179 × BW for PCAs of ≥33 weeks, and Vpanipenem = 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of ≥33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.

A Double-Blind, Crossover, Randomized Comparison of Granisetron and Ramosetron for the Prevention of Acute and Delayed Cisplatin-Induced Emesis in Patients with Gastrointestinal Cancer: Is Patient Preference a Better Primary Endpoint?

Background: Serotonin receptor antagonists are recommended by the American Society of Clinical Oncology for the prevention of acute and delayed chemotherapy-induced emesis. However, the most effective agent in this class of antiemetic drugs for preventing emesis has not been clearly defined. We therefore performed a double-blind, crossover, randomized, controlled trial comparing the efficacy of granisetron and ramosetron, using patient preference as the primary endpoint. Methods: Thirty patients receiving two courses of combined chemotherapy (including ≧60 mg/m2 cisplatin) for gastric or esophageal cancer were randomly assigned to the granisetron-ramosetron group (treatment phase 1: granisetron, 3 mg; treatment phase 2: ramosetron, 0.3 mg) or the ramosetron-granisetron group (treatment phase 1: ramosetron, 0.3 mg; treatment phase 2: granisetron, 3 mg). All patients received methylprednisolone sodium, 250 mg i.v., during each treatment phase. Results: The efficacy of granisetron and ramosetron was similar in terms of the suppression of emesis and appetite status. However, the majority of patients (19/30, 63.3%) expressed a preference for granisetron, as compared with 9 patients (30.0%) who preferred ramosetron; 2 patients (6.7%) had no preference (χ2 test: p = 0.008; Fisher’s exact test: p = 0.015). Conclusions: (1) A significant proportion of patients prefer granisetron over ramosetron for the prevention of chemotherapy-induced emesis. (2) Granisetron and ramosetron possess similar effectiveness for the suppression of emesis. (3) The variable of ‘patient preference’ should be accepted as a primary endpoint of antiemetic drug efficacy.

Population Pharmacokinetics of Transdermal Fentanyl in Patients With Cancer-Related Pain

ABSTRACT Determining the appropriate dose of transdermal fentanyl (TDF) for the alleviation of cancer pain requires determining the factors causing variations in serum fentanyl concentration after TDF treatment. The objective of this study was to identify these factors and incorporate them into a formula that can be used to predict serum fentanyl concentration after application of a TDF patch. Blood samples of cancer patients treated with a TDF patch for the alleviation of pain were collected at 24, 48, and 72 hours after application to evaluate population pharmacokinetics using the nonlinear mixed-effect model (NONMEM). Based upon this evaluation, Child-Pugh Score and use of a cytochrome P450 3A4 (CYP3A4) inducer were identified as the most significant factors in variations in serum fentanyl concentration and incorporated into the following Final Model formula: CLfenta (L/h) = 3.53 × (15 − Child-Pugh Score) × (1 + 1.38 × use or no use of CYP3A4 inducer). Bootstrap evaluation of the Final Model revealed a high convergence rate, suggesting that the model formula is a reliable and useful tool for determining TDF dose for the alleviation of cancer pain.

Population Pharmacokinetics of Oxycodone in Patients With Cancer-Related Pain

ABSTRACT Oxycodone is an opioid widely prescribed to cancer patients for pain relief. However, the pharmacokinetics of oxycodone has not been sufficiently examined. Therefore the aim of this work was to study population pharmacokinetics of oxycodone in patients with cancer pain. The authors analyzed 108 serum oxycodone samples of 33 individuals with nonlinear mixed-effects model (NONMEM). Population pharmacokinetics was calculated using the one-compartment model of clearance, volume of distribution, bioavailability, absorption constant rate, and lag time. An exponential error model was used to determine interindividual variability and a relative error model was applied to assess residual variability. Population pharmacokinetics of oxycodone at the end point were as follows: CL(L/h) = 10.7 × [1 + (2 − Child-Pugh Classification)] (Class: A = 0, B = 1, C = 2); Vd (L) = 193; ka (h−1) = 0.336; Tlag (h) = 0.859; F (%) = 63.9. Interindividual variability was CL: 30.5%, Vd: 44.6%, and F: 37.0%, and residual variability was 16.2%. As the total clearance in patients with liver dysfunction (Child-Pugh class B) was reduced to 33.3%, serum concentration of oxycodone increased by 1.5. Therefore, it became clear that dose adjustments are essential when treating patients with liver dysfunction. These findings suggest that population parameters are useful for evaluating pharmacokinetics of oxycodone in patients with cancer pain.

Clinical efficacy of arbekacin for Gram-negative bacteria

In an analysis of methicillin-resistant Staphylococcus aureus (MRSA) infected patients treated with arbekacin (ABK) only, Gram-negative bacteria (GNB) that were inhibited by low minimal inhibitory concentrations (MICs) of amikacin (AMK) or gentamycin (GM) were eradicated by the end of the ABK treatment. On the other hand, GNB that were only inhibited by high MICs of AMK or GM persisted until the end of treatment with ABK only. Thus, ABK can be expected to be effective even in cases of mixed infection with GNB and MRSA.

Evaluation of Renal Adverse Effects of Combination Anti-retroviral Therapy including Tenofovir in HIV-infected Patients

PURPOSE In order to maintain plasma HIV-RNA concentration in HIV-infected patients, below the detection limit combination anti-retroviral therapy (cART) are used. Although the nucleoside/nucleotide reverse transcriptase inhibitor, tenofovir disoproxil fumarate (TDF) is a first-line drug commonly used, it is associated with renal dysfunction. Nevertheless, only few clinical studies have focused on TDF in combination with new anti-HIV drugs, including the protease inhibitor (PI) darunavir (DRV), or the integrase strand transfer inhibitor (INSTI) raltegravir (RAL). Here we report the influence of such cART involving TDF on renal function. METHODS We retrospectively investigated 68 patients under cART that included TDF between November 2004 and May 2012. We used hospital records to establish each patients background and characteristics, CD4 cell count, plasma HIV-RNA concentration, drug combinations, renal function, and anti-retrovial therapy history. RESULTS In all patients who had received cART, the plasma HIV-RNA concentration had fallen to less than 40 copies/mL by week 24 after the start of the therapy, and an increase in the CD4 cell count was observed. For each drug used in combination with TDF, the plasma HIV-RNA concentration and CD4 cell count showed a similar trend. After week 12, the estimated glomerular filtration rate (eGFR) had significantly decreased in all patients. The eGFR was significantly lower in those received PI on week 24 and in those received INSTI on week 12. The eGFR was significantly reduced in PI group who received atazanavir + ritonavir (ATV/RTV) on week 60. The eGFR in the DRV/RTV group tended to decrease. The eGFR in the PI and ATV/RTV group was significantly lower than in the efavirenz (EFV) group on week 96. CONCLUSION It selecting drugs to include in combination therapy of HIV-infected patients, consideration should be given to the risk of renal dysfunction. There is a need to monitor renal function when TDF is combined with ATV/RTV, DRV/RTV or RAL.

Epinephrine administered with lidocaine solution does not worsen intrathecal lidocaine neurotoxicity in rats.

Background Epinephrine can potentially worsen the neurotoxic effects of local anesthetics when used for spinal or epidural anesthesia. The vasoconstrictive property of epinephrine reduces dural blood flow, which in turn reduces the clearance of local anesthetics from the subarachnoid space. This study examined the histological and neurofunctional effects of intrathecally administered lidocaine combined with epinephrine in rats. Methods Sixty-two rats were divided into 9 treatment groups: 5% or 7.5% lidocaine in 10% glucose solution with or without 0.1 or 0.5 mg/mL epinephrine, or epinephrine alone at 0.1 or 0.5 mg/mL in 10% glucose, or 10% glucose alone. Hind-limb motor function was evaluated immediately after drug injection by walking behavior. Sensory function was assessed by the response to radiant heat stimulation at just before and 1 week after the injection. Seven days after the injection, L3 spinal cord with anterior and posterior roots, the dorsal ganglion, and cauda equina were harvested and examined histologically. Results Histological lesions were limited to the posterior root just at entry into the spinal cord in rats injected with 7.5% lidocaine, with and without epinephrine. No histological abnormalities were noted in other areas or other groups. There was no significant change in sensory threshold in all groups. Significantly, prolongation of gait recovery time was noted in 5% and 7.5% lidocaine with epinephrine groups compared with 5% or 7.5% lidocaine alone. Conclusions Intrathecal epinephrine prolonged the action of intrathecal lidocaine but did not worsen lidocaine-induced histological damage and functional impairment.

Simplified Pyrogen Test

Japanese Pharmacopoeia (J. P.) requires that the pyrogen test is essential for parenteral solutions. But, in hospital pharmacy, it is practically impossible to perform the official test because of the difficult control of test animals, limited laboratory facilities and timeconsuming procedures. In the study for a simplified checking, a method better than the J. P. pyrogen test was found. The method requires Limulus Lysate, a blood component of Limulus, which is presently applied for the quantitative analysis of endotoxin. The result of this study indicates the possibility of checking pyrogens in parenteral solutions prepared at a hospital pharmacy.