International journal of clinical pharmacology and therapeutics (INT J CLIN PHARM TH)

Publisher: Dustri-Verlag

Journal description

The International Journal of Clinical Pharmacology and Therapeutics appears monthly and publishes manuscripts containing original material with emphasis on the following topics: Clinical trials, Pharmacoepidemiology - Pharmacovigilance, Pharmacodynamics, Drug disposition and Pharmacokinetics, Quality assurance, Pharmacogenetics, Biotechnological drugs such as cytokines and recombinant antibiotics. Case reports on adverse reactions are also of interest.

Current impact factor: 1.22

Impact Factor Rankings

2015 Impact Factor Available summer 2016
2014 Impact Factor 1.223
2013 Impact Factor 1.044
2012 Impact Factor 1.2
2011 Impact Factor 1.183
2010 Impact Factor 1.189
2009 Impact Factor 1.381
2008 Impact Factor 1.299
2007 Impact Factor 1.281
2006 Impact Factor 1.361
2005 Impact Factor 1.755
2004 Impact Factor 1.414
2003 Impact Factor 0.923
2002 Impact Factor 1.471
2001 Impact Factor 1.351
2000 Impact Factor 1.222
1999 Impact Factor 0.871
1998 Impact Factor 0.77
1997 Impact Factor 0.519
1996 Impact Factor 0.828
1995 Impact Factor 0.607
1994 Impact Factor 0.424
1993 Impact Factor 0.37
1992 Impact Factor 0.756

Impact factor over time

Impact factor

Additional details

5-year impact 1.17
Cited half-life 8.00
Immediacy index 0.24
Eigenfactor 0.00
Article influence 0.31
Website International Journal of Clinical Pharmacology & Therapeutics website
Other titles International journal of clinical pharmacology and therapeutics, Clinical pharmacology and therapeutics
ISSN 0946-1965
OCLC 29934177
Material type Periodical
Document type Journal / Magazine / Newspaper

Publisher details


  • Pre-print
    • Archiving status unclear
  • Post-print
    • Archiving status unclear
  • Conditions
    • We have contacted this publisher on multiple occasions, and have not been able to obtain a response to our enquiries. If you have any information on this publisher's policy, please submit an update using the form below.
  • Classification
    ​ white

Publications in this journal

  • International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202349
  • Joaquín Borrás-Blasco · Elvira Casterá · Xavier Cortes · Juan Martín-Alonso · J Dolores Rosique-Robles · F Javier Abad
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: In January 2011, a biological therapies commission was created in our hospital to fully address the management of biological drugs. A biological therapy prioritization protocol was developed for ankylosing spondylitis (AS) patients. Here, we describe it and report on its economic impact to illustrate how we are optimizing the use of these expensive new drugs. Methods: The biological therapies commission established several procedures for the rational use of biological drugs such as cost-efficiency therapeutic protocols, pharmacovigilance, and therapeutic drug monitoring programs. The AS protocol was based on clinical and economic aspects. We estimated the economic impact of the protocol by comparing the cost of treating AS patients with biological drugs in the pre-commission (2009 - 2010) vs. post-commission period (2011 - 2013). AS patients treated with adalimumab (ADA), etanercept (ETN) or infliximab (IFX) for at least 6 months in the 2009 - 2013 period were included. Results: 107 patients were included. In the pre-commission period, total expenses increased by +30,944 € (+4%). After protocol implementation, total expenses decreased by 11,441 € (-1%) during 2011, and by an additional 36,781 € (-4%) and 53,872 € (-8%) in 2012 and 2013, respectively. In the 2010 - 2013 period the cost of biological therapy per patient-year decreased by 869 €, suggesting the positive effects of the biological therapy prioritization protocol instauration. Conclusion: We describe the establishment of a multidisciplinary biological therapy commission to optimize the use of biological therapies. We illustrate its work in developing a protocol for the management of AS patients with such therapies. We show that after 3-years of implementation, the biological therapy prioritization protocol allowed us to steadily decrease the direct cost of biological drug therapies per patient, up to 869 €.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202410
  • International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202443
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: This study was designed to investigate patient responses to a medication counseling intervention program piloted by the National Health Insurance Service (NHIS), the national health insurer in Korea, to improve medication management in patients with hypertension, hyperlipidemia, or diabetes. Methods and materials: Interventions were conducted from July to September 2013 through direct mailing followed by two telephone-initiated counseling sessions for the medication discontinuation group (< 80% medication possession ratio (MPR) and ≥ 2 months of discontinuation) and the medication over-possession group (≥ 150% MPR). The telephone intervention was applied through two models: model 1 (counseling by NHIS staff only) and model 2 (counseling by NHIS staff with contract-based working pharmacists in community pharmacies). Multivariate logistic regression analysis was performed to identify factors affecting favorable responses of patients to the telephone-initiated intervention. Patient responses to the telephone-initiated intervention were evaluated by a counselor. Results: In all, 891 patients were counseled via telephone. Patient responses to the telephone-initiated intervention were favorable in 57.6%, neutral in 17.4% and not favorable in 24.9% overall. Counseling by NHIS staff together with pharmacists (model 2) produced more favorable responses from patients than counseling by NHIS staff alone (model 1) (OR 2.73, 95% CI 1.97 - 3.77). Conclusion: Our findings of favorable responses to interventions support a personalized approach by the NHIS to improve patient behavior for medication adherence.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202409
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Acetyl-L-carnitine (ALC) has demonstrated neuroprotective effects in several experiments and is widely prescribed to reduce cognitive impairment in Alzheimer's disease patients or manage neuropathic symptoms in diabetic patients. Objectives: This study was designed to assess the pharmacokinetic (PK) bioequivalence between a new generic (test) formulation of ALC hydrochloride 590 mg and a branded (reference) formulation of ALC hydrochloride 590 mg in healthy Korean male volunteers. Methods: This was a randomizedsequence, single-dose, two-way crossover study. All subjects randomly received one formulation of the test or reference tablet and the other formulation with a 7-day washout period. Blood samples (7 mL) were collected immediately before dosing, and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 12 hours postdose. The plasma concentrations of ALC were analyzed using liquid chromatography tandem mass spectrometry. Tolerability was assessed throughout the study. Results: The PK profiles of both formulations showed similar rends. The mean (± SD) baseline (predose) concentration of ALC was 1.23 ± 0.31 μg/mL and 1.09 ± 0.30 μg/mL for the test and the reference formulations, respectively. The mean Cmax for the test and reference formulations were 1.74 ± 0.43 μg/mL and 1.68 ± 0.48 μg/mL, respectively. The mean AUClast of ALC was 12.96 ± 1.89 μg×h/mL and 12.49 ± 2.44 μg×h/mL for the test and reference formulations, respectively. The geometric mean ratios of test/reference (90% CI) were 1.050 (0.960 - 1.149) for Cmax and 1.048 (1.000 - 1.099) for AUClast. Both formulations were well tolerated in all treatment groups. Conclusion: The test and the reference formulations of ALC were bioequivalent with regard to the PK parameters.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202381
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. Methods: 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. Results: GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. Conclusions: These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202391
  • International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CPXCES14EA07
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: To evaluate the effect of liraglutide and NPH on blood glucose fluctuations in patients with newly diagnosed type 2 diabetes mellitus (T2DM). Methods: A total of 63 newly diagnosed T2DM patients were randomized into a liraglutide group and an NPH group. They were treated for 12 weeks. The values of CGM, HbA1C, and BMI were measured and compared before and after treatment. Results FPG, HbAlc, and MBG were decreased in both groups after 12 weeks of treatment. In the liraglutide group, the MAGE, SDBG, LAGE, BMI, and waist circumference were significantly 1ower than in the NPH group (p < 0.05). Patients in the liraglutide group had a greater incidence of gastrointestinal adverse effects than in the NPH group (p < 0.05). The incidence of hypoglycemia episode in the liraglutide group was significantly lower than in the NPH group (p < 0.05). Conclusions: Liraglutide achieved improvements in overall glycemic control similar to NPH in patients with newly diagnosed T2DM. Liraglutide was associated with less glucose fluctuation than NPH treatment as assessed by CGM. In addition, patients in the liraglutide group had a greater incidence of gastrointestinal adverse effects, a lower incidence of hypoglycemia, and some weight reduction.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202415
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: To determine whether a potential pharmacokinetic interaction exists between perindopril arginine 5 mg and amlodipine 5 mg, after administration as a fixed-combination of perindopril 5 mg/amlodipine 5 mg (S05985). Methods: A total of 30 subjects was enrolled into this single center, open-label, randomized, 3-period cross-over study and was randomized to receive 1 tablet of S05985, 1 tablet of perindopril tert-butylamine 4 mg, or 1 tablet of amlodipine 5 mg. The doses of both perindopril salts correspond to 3.34 mg of perindopril expressed as free acid. Serial blood samples were collected in each treatment period for determination of plasma amlodipine, perindopril, and perindoprilat concentrations and for calculation of the respective pharmacokinetic parameters (AUC0-∞, AUC0-t, Cmax, and tmax). Statistical analyses of the pharmacokinetic parameters included ANOVA and calculations of 90% confidence intervals for the ratio of the geometric means for Cmax, AUC0-t, and AUC0-∞. Safety was also assessed. Results: A total of 29 subjects completed the study per protocol. There was no serious adverse event. All 90% confidence intervals for Cmax, AUC0-t, and AUC0-∞ for perindopril, perindoprilat, and amlodipine were within the limits (80.00 - 125%), indicating that both treatments were bioequivalent. Conclusion: These results indicate that no drug-drug interaction exists after single-dose oral administration of S05985 (perindopril 5 mg and amlodipine 5 mg) when compared to single-dose administration of each component alone, i.e., perindopril tert-butylamine 4 mg and amlodipine 5 mg, given separately.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202250
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: The aim of the present study is to investigate factors affecting intrasubject variability of pharmacokinetic (PK) exposure, which affect the results of bioequivalence (BE) studies. We focused on two factors: absolute oral bioavailability (BA) and acidic nature of drugs. Methods: Intrasubject coefficient of variation (CV) for Cmax and AUC was estimated based on the 90% confidence intervals (CIs) and the number of subjects from fasting BE study results for our investigation. Relationships between the intrasubject CV and the absolute oral BA as well as the acidic nature of the drugs were investigated. Results: First, the relationship between absolute oral BA and intrasubject variability of PK exposure (Cmax and AUC) showed negative log-linear relationship in the BE studies following oral administration of 65 immediate-release drugs under fasted condition. Drugs with poor absolute oral BA of less than 5% showed high intrasubject CV in the range of 30 - 65%. In contrast, drugs with high absolute oral BA of more than 80% showed low intrasubject CV of less than 20%. Second, acidic drugs with pKa < 6 had higher intrasubject CV of Cmax than AUC compared to other types of drugs. The intrasubject CV ratios of Cmax to AUC for acidic drugs with pKa < 6 were significantly higher than those for other types of drugs. Conclusion: Results show that absolute oral BA is one of the major factors that predict the extent of intrasubject variability of PK exposure. Acidic nature of drugs is thought to be an additional factor increasing intrasubject variability of Cmax as compared to AUC.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202399
  • [Show abstract] [Hide abstract]
    ABSTRACT: To characterize the absorption, distribution, metabolism, and excretion of naloxegol, a PEGylated derivative of the µ-opioid antagonist naloxone, in healthy male subjects. [14C]-Labeled naloxegol (27 mg, 3.43 MBq) was administered as an oral solution to 6 fasted subjects. Blood, fecal, and urine samples were collected predose and at various intervals postdose. Naloxegol and its metabolites were quantified or identified by liquid chromatography with radiometric or mass spectrometric detection. Pharmacokinetic parameters were calculated for each subject, and metabolite identification was performed by liquid chromatography with parallel radioactivity measurement and mass spectrometry. Naloxegol was rapidly absorbed, with a maximum plasma concentration (geometric mean) of 51 ng/mL reached before 2 hours after dosing. A second peak in the observed naloxegol and [14C] plasma concentration-time profiles was observed at ~ 3 hours and was likely due to enterohepatic recycling of parent naloxegol. Distribution to red blood cells was negligible. Metabolism of [14C]-naloxegol was rapid and extensive and occurred via demethylation and oxidation, dealkylation, and shortening of the polyethylene glycol chain. Mean cumulative recovery of radioactivity was 84.2% of the total dose, with ~ 68.9% recovered within 96 hours of dosing. Fecal excretion was the predominant route of elimination, with mean recoveries of total radioactivity in feces and urine of 67.7% and 16.0%, respectively. Unchanged naloxegol accounted for ~ 1/4 of the radioactivity recovered in feces. Naloxegol was rapidly absorbed and cleared via metabolism, with predominantly fecal excretion of parent and metabolites.
    International journal of clinical pharmacology and therapeutics 09/2015; 53(10). DOI:10.5414/CP202276
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study aims to evaluate the effectiveness and tolerability of esomeprazole and omeprazole in patients with gastroesophageal reflux disease (GERD). Electronic searches on PubMed, EMBASE, the Cochrane Library, and databases were carried out for reports up to February 28, 2015. Ten eligible studies from 8 articles were found that enrolled a total of 10,286 patients for meta-analysis. These results revealed a significant difference between esomeprazole vs. omeprazole (RR = 1.06, 95% CI [1.01, 1.10], I2 = 72%, p = 0.01) by subgroup according to dosage by random effects model, and a significant difference between esomeprazole 40 mg vs. omeprazole 20 mg (RR = 1.07, 95% CI [1.004, 1.14], I2 = 78%, p = 0.04) based on healing rate as determined by endoscopy, using a random effects model. A significant difference between esomeprazole 20 mg and omeprazole 40 mg (RR = 0.68, 95% CI [0.47, 0.97], I2 = not applicable, p = 0.03) was also found in comparing relief of symptoms by random effects model. There were no significant differences in outcomes between other subgroups, including tolerability. Based on these results, a high dose of esomeprazole is recommended for GERD treatment and control in adults.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202396
  • [Show abstract] [Hide abstract]
    ABSTRACT: As hypertension and dyslipidemia are frequent comorbidities, antihypertensive drugs and lipid-lowering agents are often prescribed together for their treatment. Telmisartan and rosuvastatin are widely used together to treat hypertension and dyslipidemia. A combination formulation of these two drugs would improve patient compliance due to ease of dosing. The purpose of this study was to assess bioequivalence of single-dose administration of a newly-developed fixed-dose combination (FDC) tablet containing telmisartan/rosuvastatin 80/20 mg (test treatment) and coadministration of a telmisartan 80-mg tablet and a rosuvastatin 20-mg tablet (reference treatment) in healthy Korean male volunteers. This was a single-dose, randomized, open-label, 2-period crossover study enrolling healthy males aged 20 - 50 years with BMI between 18.5 and 25 kg/m2. Each subject received a single dose of the reference and test treatments with a 14-day washout period. Blood sampling was performed at prespecified intervals for up to 72 hours after dosing. Primary pharmacokinetic parameters were Cmax, AUClast, and AUC0-∞ of telmisartan, rosuvastatin, and N-desmethyl rosuvastatin. Bioequivalence was assessed by determining whether the 90% confidence intervals (CIs) of the geometric mean ratios (test treatment/reference treatment) of these parameters were within the standard range of 80% to 125%. Adverse events were monitored via regular interviews with the subjects and by physical examinations. 60 subjects were enrolled and 55 completed the study. The 90% CIs of the geometric mean ratios of Cmax, AUClast, and AUC0-∞ were 0.9262 - 1.1498, 0.9294 - 1.0313, and 0.9312 - 1.0320 for telmisartan, 0.9041 - 1.0428, 0.9262 - 1.0085, and 0.9307 - 1.0094 for rosuvastatin, and 0.8718 - 1.0022, 0.8901 - 0.9904, and 0.8872 - 0.9767 for N-desmethyl rosuvastatin, respectively. There was no statistical difference in the incidence of adverse events (AEs) (all of which were mild or moderate) between the reference and test treatments. Our findings suggest that the telmisartan/rosuvastatin FDC is bioequivalent to coadministration of separate tablets, and both treatments were safe and well tolerated. Administration of this FDC tablet is expected to improve patient compliance.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202412
  • [Show abstract] [Hide abstract]
    ABSTRACT: Transparency and evidence-based medicine are cornerstones of good publication practices (GPP), and concern publishers, editors, research investigator, and reviewers alike. Methods for implementing these principles within the framework of GPP are described. The main aspects include obtaining a Manuscript Agreement Contract, a Statement on Transparency of Authorship and a Declaration of Conflicts of Interest from the authors. Assessing whether a manuscript meets the requirements of EBM is demonstrated using the "7-D assessment". The main purpose of this tool is to established that the (1) right Design, (2) right Diagnosis, (3) right Drug molecule, (4) right Dosage, (5) right Data, (6) right Deductions, and (7) right Documentation have been implemented in order to meet the objectives of the investigation. If the findings from any one of these assessments is questionable, the compliance of the research with EBM principles will be weakened and the reviewers and editors will make recommendations to the publisher accordingly. The guidelines described will help to provide a fair and transparent process of scientific publication and foster the freedom of clinical pharmacological research.
    International journal of clinical pharmacology and therapeutics 09/2015; DOI:10.5414/CP202421
  • [Show abstract] [Hide abstract]
    ABSTRACT: The oral retinoid agent isotretinoin (13-cis-retinoic acid) is approved for the treatment of severe recalcitrant cystic acne. For registrational renewal of Oratane® in Mexico (isotretinoin; Laboratorios Dermatológicos Darier S.A. de C.V., Mexico), it was necessary to establish bioequivalence to the reference product Roaccutan® (Isotretinoin; Roche, Mannheim, Germany). Three prior studies failed to establish the bioequivalence of Oratane to Mexican-sourced Roaccutan. However, 13 studies demonstrated the bioequivalence of Oratane to Roaccutane® from multiple sources. This study compared the bioavailability of Oratane with that of Mexican-sourced Roaccutan and Australian-sourced Roaccutane. Study participants received each of the three agents in a randomized, open-label, 6-sequence, 3-way crossover study with a 2-week washout period between treatments. Pharmacokinetic analysis revealed that peak plasma concentration (Cmax) and area under the plasma concentration-time curve from time 0 (dosing) to infinite time (AUC0-∞) were lower for Roaccutan than for Roaccutane and Oratane (Cmax: 1,023.35, 1,223.08, and 1,224.25 ng/mL, respectively; AUC0-∞: 13,653.65, 15,681.35 and 15,733.55 ng/mL×h, respectively). The 90% CIs (test/reference) for the ratios of the geometric means indicated that Oratane was bioequivalent to Roaccutane but not to Roaccutan. In addition, Roaccutane (R2) was not bioequivalent to Roaccutan (R1; R1/R2 90% CIs: Cmax, 76.12 - 91.04; AUC0-t, 82.19 - 91.13; AUC0-∞, 82.94 - 91.57). Oratane and Australian-sourced Roaccutane could be considered bioequivalent, but neither formulation was found to be bioequivalent to Mexican-sourced Roaccutan.
    International journal of clinical pharmacology and therapeutics 08/2015; DOI:10.5414/CP202299
  • International journal of clinical pharmacology and therapeutics 08/2015; DOI:10.5414/CPXCES14EA05
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Statins have been reported to exert anti-inflammatory effects, but the association between statins and acute lung injury (ALI) remains controversial. Thus, we performed a meta-analysis of all published randomized controlled trials (RCTs) aiming to summarize and evaluate the current evidence about the potential use of statins in ALI patients. Method: We searched for articles that focused on the association between statins and ALI-related outcomes through electronic databases until December 10th, 2014. The inclusion of articles, quality appraisal of included studies, and data extraction were performed by two investigators. Eligible articles were analyzed by Review manager 5.2 and STATA 12.0 software. Results: Data from 1,778 patients in five randomized controlled clinical trials were analyzed. No differences in intensive care unit (ICU) mortality (RR = 0.88, 95% CI = 0.63 - 1.22, p = 0.44), hospital < mortality (RR = 1.00, 95% CI = 0.85 - 1.17, p = 0.97) and mechanical ventilation duration (MD = -0.40, 95% CI = -1.52 - 0.71, p = 0.48) were observed between the experimental and control groups. Conclusions: According to large and high-quality published clinical trials as also summarized by the present meta-analysis, there is insufficient evidence to support the use of statins in ALI patients.
    International journal of clinical pharmacology and therapeutics 08/2015; DOI:10.5414/CP202340
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study assessed the pharmacokinetics and tolerability of fingolimod and its metabolites in severe renal impairment and healthy subjects. In this single-dose, open-label study, 9 severe renal impairment subjects and 9 demographically matched healthy subjects were included. Each subject received a single oral dose of fingolimod 1.25 mg, and their blood and urine samples were assessed. The pharmacokinetics of fingolimod and its metabolites, fingolimod-phosphate (active metabolite, fingolimod-P), M2, and M3, were compared in both groups. Safety and tolerability were also assessed. In severe renal impairment subjects, mean ± standard deviation values of Cmax (ng/mL) of fingolimod and fingolimod-P were 0.878 ± 0.256 and 1.13 ± 0.293 vs. 0.653 ± 0.138 and 0.904 ± 0.229 in healthy subjects, respectively. The overall drug exposures (AUCinf (ng×h/mL)) for fingolimod and fingolimod-P were 131 ± 90.7 and 75.5 ± 33.6 in severe renal impairment subjects vs. 82.3 ± 36.9 and 65.9 ± 30.6 in healthy subjects, respectively. t1/2 (hours) for fingolimod and fingolimod-P was comparable in severe renal impairment subjects (94 ± 53 and 95 ± 50) and healthy subjects (85 ± 25 and 101 ± 46). All adverse events were as expected for fingolimod 1.25 mg. The exposure to fingolimod and fingolimod-P was moderately increased (90% CI, 0.94 - 2.18) in severe renal impairment subjects, while half-lives and protein binding were similar to those in healthy subjects. Given that these changes are not clinically meaningful, fingolimod dose adjustment is considered unnecessary in patients with mild, moderate, or severe renal impairment.
    International journal of clinical pharmacology and therapeutics 08/2015; DOI:10.5414/CP202356
  • [Show abstract] [Hide abstract]
    ABSTRACT: Tenofovir is an efficacious drug with a long half-life and high activity against both HIV and HBV. However, the pharmacokinetics of tenofovir have not been studied in HIV/HBV co-infected patients. Data from HIV mono-infected patients may not be transferable to HIV/HBV co-infected population because the nature and consequences of the co-infection are different. This study developed a population pharmacokinetic model of tenofovir in patients with HIV/HBV co-infection and identified pathophysiologic factors that affect the pharmacokinetics of the drug. Sparse and intensive blood samples were collected from patients with HIV/HVB coinfection. The population pharmacokinetic model of tenofovir was developed by a nonlinear mixed-effects modeling approach (NONMEM®). A total of 332 tenofovir plasma concentrations from 146 patients were obtained. A two-compartment model best described the pharmacokinetics of tenofovir. Creatinine clearance (estimated by Cockcroft and Gault equation) affected the tenofovir apparent clearance (CL/F). Tenofovir CL/F decreased by 23.5% when concomitantly used with atazanavir/ritonavir. Based on the results from our study, it was shown that the pharmacokinetics of tenofovir in HIV/HBV co-infected patients are comparable to those with HIVmonoinfection. This study confirmed that patients with kidney impairment and the concurrent use of atazanavir/ritonavir will require the dosage of tenofovir to be adjusted to ensure efficacy and prevent unwanted toxicities. The developed model can reliably be used to adjust for the dosage of tenofovir in this population, especially when therapeutic drug monitoring services are unavailable.
    International journal of clinical pharmacology and therapeutics 08/2015; DOI:10.5414/CP202386
  • [Show abstract] [Hide abstract]
    ABSTRACT: To evaluate the cardiac and pulmonary effects of siponimod (BAF312) and propranolol co-administration in healthy subjects. Healthy subjects (n = 76) were randomized in a doubleblind manner to receive propranolol at siponimod steady state (group A), siponimod at propranolol steady state (group B), placebo (group C) and propranolol (group D). Pharmacodynamic evaluations included maximum change from baseline in time-matched hourly average heart rate (Emax HR) and mean arterial blood pressure (Emax MABP) over 24 hours postdose, change from baseline in PR intervals, cardiac rhythm, and forced expiratory volume in 1 second (FEV1). Pharmacokinetic and safety parameters were also assessed. Siponimod and propranolol when administered alone resulted in similar HR decrease at steady state. Compared to propranolol alone, the combination at steady state had an additional 6.21 bpm (95%CI: 2.32, 10.11) decrease of mean EmaxHR, a decrease of 5.04 bpm (0.52, 9.56) for group A and 7.39 bpm (2.87, 11.90) for group B. A minor decrease in MABP and a trend towards PR interval increase were noted with co-administration treatment vs. propranolol alone. There were no episodes of second-degree atrioventricular blocks or sinus pauses > 3 seconds. Baseline-corrected FEV1 was reduced by -0.07 L (95% CI: -0.17, 0.03) for group A and -0.05 L (-0.15, 0.05) for group B vs. propranolol alone. There were no cardiovascular adverse events during coadministration treatment. Coadministration of siponimod and propranolol was well tolerated. Bradyarrhythmic effects were less pronounced when propranolol was added to siponimod steady-state therapy compared with siponimod addition to propranolol.
    International journal of clinical pharmacology and therapeutics 08/2015; DOI:10.5414/CP202369