Volume 46, No. 4/2008(April)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Pharmacokinetics
Cefepime in intensive care unit patients: Validation of a population pharmacokinetic approach and influence of covariables
Abstract
B. Georges, J.-M. Conil, T. Seguin, E. Dieye, P. Cougot, J.-F. Decun, M. Lavit, K. Samii, G. Houin and S. Saivin
1Anesthésie Réanimation, CHU Rangueil, and 2Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, Toulouse, France
Aim: The purpose of our study was to define and validate a population-pharmacokinetic model including the influence of patients’ characteristics on the pharmacokinetics of cefepime. Patients and methods: A total of 55 patients were randomized in Group 1 (34 patients, 320 cefepime concentrations) for the model building and Group 2 (21 patients, 196 cefepime concentrations) for the validation group. They received cefepime as 2 g × 2 or as 4 g continuously. The population pharmacokinetic analysis was carried out using NONMEM and a baseline model was constructed for studying the influence of demographic and biological variables. The model was then validated by a comparison of the predicted and observed concentrations in Group 2. A final model was elaborated from the whole population. Results: Total clearance (CL) was significantly correlated with the serum creatinine (CREA) and the central volume of distribution (V1) was correlated with the body weight (WT). The final model was: CL = 7.14 + (–0.0133 × CREA). V1 = (–16.8) + (0.475 × WT). Q (intercompartmental clearance) = 10.5. V2 = 18.1. The mean pharmacokinetic parameters and their individual variability were: CL (8.24 l/h, 45%), V1 (20.89 l, 60%), V2 (17.95 l, 49%), total volume (38.85 l, 42%) and Q (10.56 l/h, 9%). The bias (1.07 mg/l, IC 95% = –40.46 – +42.60), precision (21.19%) and AFE (1.15) demonstrated the performance of the model. Conclusion: We have developed and validated a pharmacokinetic model to estimate cefepime concentrations. We showed that serum creatinine and body weight are factors that may influence the standard dose of cefepime. Our model enabled us to predict cefepime concentrations in other patients.Correspondence to:
Dr. S. Saivin; Laboratoire de Pharmacocinétique et Toxicologie Clinique, Institut Fédératif de Biologie, 330 Avenue de Grande Bretagne, TSA 40031, 31059 Toulouse Cedex 9, France
Email: saivin.s@chu-toulouse.fr
Pharmacokinetics
Cyclosporine safety and bioavailability with two second-generation softgel capsules using serum concentrations/TDM and modeling in transplant patients – a retrospective, parallel, comparative evaluation study
Abstract
R. Berger, A. Avramoff, M. Leiba, A.J. Domb, A. Laor and A. Nagler
1Institute of Oncology and Radiotherapy, Sheba Medical Center, Tel Hashomer, 2Department of Medicinal Chemistry, School of Pharmacy-Faculty of Medicine, The Hebrew University, Jerusalem, 3Dexxon’s Center for Pharmacokinetic Evaluations, Or-Akiva, 4Division of Hematology and Bone Marrow Transplantation, Sheba Medical Center, Tel Hashomer and 5Department of Internal Medicine A, Carmel Medical Center, Haifa, Israel
Objective: Deximune® soft-gelatin capsules (Dexcel Ltd., Hadera, Israel), the test preparation and Sandimmun Neoral® (Novartis Inc., Basel, Switzerland), the reference preparation, are two cyclosporine (CyA) formulations widely used after stem cells and solid organ transplantation. A post-marketing, retrospective, parallel, comparative, multicenter survey study in transplant patients receiving these two formulations after transplantation was carried out in order to compare the toxicity profile and bioavailability. Materials and methods: The study was conducted in the five main leading transplantation centers in Israel and included 174 patients. A total of 1 – 3 CyA serum levels at different periods after transplantation were measured in each subject and the bioavailability, efficacy and toxicity profile were assessed. The blood concentrations were compared using a statistical model after adjustment for type of transplantation, dose and time after transplantation as confounding factors. Results: No distinct differences were observed between the two CyA formulations. Using model-derived least squares means (LSM) of the CyA blood levels and adjusting for relevant confounding factors, no significant difference could be found between the blood levels of the test and reference formulations. Most of the side effects were mild and transient with both formulations, whereas 23% of the patients reported serious adverse events (mainly hypertension, 15%). 20% of the patients developed infectious complications during the therapy. Conclusions: Deximune® administration is safe. The toxicity profile of the product, incidence and type of side effects and bioavailability are similar to those of Sandimmun Neoral®.Correspondence to:
Prof. A. Nagler; Director Division of Hematology, BMT & CBB, Chaim Sheba Medical Center, Tel Hashomer, 52621, Israel
Email: w-a.nagler@sheba.health.gov.il
Pharmacokinetics
Tolerability and pharmacokinetics of antofloxacin hydrochloride after multiple oral dose administration in healthy Chinese male volunteers
Abstract
Y. Xiao, Y. Lu, Z. Kang, F. Hou, S. Wang, T. Li, Y. Liu and Y. Xia
Institute of Clinical Pharmacology, First Hospital, Peking University, Beijing, China
Objective: To evaluate the tolerability and pharmacokinetics characteristics of antofloxacin hydrochloride, a fluoroquinolone developed in China, after multiple oral doses in healthy male Chinese volunteers. Methods: 13 subjects took 300 mg of antofloxacin hydrochloride once daily for 7 days. Safety was evaluated on Days 0, 2, 4 and 8. Blood and urine samples for pharmacokinetics analysis were taken at designated time points. HPLC was used to assay the serum and urine concentration of antofloxacin. Results: A total of 12 subjects completed the trial and 1 volunteer was dropped because of a skin rash 2 h after the drug was administered. 1 volunteer had a prolonged prothrombin time (PT), another had a serum alanine aminotransferase (ALT) elevation and a third had increases in aspartate aminotransferase (AST) and γ-glutamyltransferase (γ-GT). No other complaints were reported during the trial. The steady state serum concentration on a daily 300 mg oral dose was obtained at 96 h. The pharmacokinetics parameters at steady state were: tmax 1.19 ± 0.59 h, Cmax 4.49 ± 0.81 mg/l, Cmin 1.35 ± 0.33 mg/l, AUCss 74.74 ± 12.58 mg/l × h, Cav 3.11 ± 0.52 mg/l, t1/2β 20.75 ± 2.93 h, PTF 102.13 ± 23.92%. The urinary elimination of antofloxacin over 120 h after the last dose was approximately 62%. Cmax in steady state was 50% higher compared to data for Day 1 after a single dose administration. Conclusions: The results indicated that 300 mg antofloxacin hydrochloride once daily oral administration is safe, but can lead to high drug concentrations. This should be evaluated further.Correspondence to:
Y. Xiao, MD, PhD; Institute of Clinical Pharmacology, Peking University, 38#, Xueyuan Road, Haidian District, Beijing, 100083, China
Email: xiaoyonghong@bjmu.edu.cn
Pharmacodynamics
Impact of naproxen sodium at over-the-counter doses on cyclooxygenase isoforms in human volunteers
Abstract
B. Hinz, O. Cheremina, D. Besz, S. Zlotnick and K. Brune
1Institute of Toxicology and Pharmacology, University of Rostock, Rostock and 2Department of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany and 3Bayer HealthCare, Morristown, NJ, USA
Objective: Over the last few years, there has been concern regarding the cardiovascular safety of selective cyclooxygenase (COX)-2 inhibitors and high-dose regimens of nonsteroidal anti-inflammatory drugs (NSAIDs). On the other hand, those compounds which elicit an almost complete (> 95%) and continuous suppression of platelet COX-1 may represent an exception. Apart from aspirin, which irreversibly inactivates COX-1, high-dose naproxen causes sustained COX-1 inhibition throughout the dose interval in some individuals. The present study examines whether naproxen sodium after a single dose administration and at steady state using “over-the-counter (OTC) doses” produces sufficient COX-1 inhibition. COX-2 inhibition was assessed concomitantly. Methods: Ex vivo inhibition of COX enzymes and the pharmacokinetics of naproxen were assessed in four volunteers receiving 220 mg naproxen sodium b.i.d. for 7 days. Blood samples were obtained pre-dose, at specified time points after the first dose on Day 1, and 12 hours after the previous evening dose on Days 2, 3, 4, 5 and 8. Recovery was assessed up to 36 hours after the last dose. Coagulation-induced thromboxane B2 formation and lipopolysaccharide-induced prostaglandin E2 synthesis were measured ex vivo in human whole blood as indices of COX-1 and COX-2 activity. Results: Maximal inhibition after a single dose and at steady state were as follows: 94% and 93% (COX-1), and 79% and 85% (COX-2). A greater than 95% COX-1 inhibition was observed transiently in 2 of 4 volunteers at the time of maximal plasma concentration after a single-dose administration and in 1 of 4 volunteers throughout the 12-hour dose interval at steady state. For both isoenzymes, COX inhibition correlated with naproxen plasma levels (ex vivo IC50 values of 35.48 µmol/l (COX-1) and 64.62 µmol/l (COX-2)). Conclusions: Administration of naproxen sodium at OTC doses was associated with a profound inhibition of both COX enzymes. Although low-dose naproxen may elicit a virtually complete COX-1 inhibition in some individuals, it does not mimic the reliable, sustained and complete COX-1 blockade produced by aspirin. In conclusion, prolonged treatment with 220 mg naproxen sodium b.i.d. is not expected to provide sufficient cardioprotection in all patients, but may influence platelet function in some.Correspondence to:
Dr. B. Hinz; Institute of Toxicology and Pharmacology, University of Rostock, Schillingallee 70, 18057 Rostock, Germany
Email: burkhard.hinz@med.uni-rostock.de
Pharmacodynamics
Acarbose alleviates rise in plasma uric acid concentration induced by sucrose ingestion
Abstract
Y. Moriwaki, T. Kobayashi, T. Inokuchi, A. Yamamoto, S. Takahashi, T. Ka, Z. Tsutsumi and T. Yamamoto
Division of Endocrinology and Metabolism, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
Sucrose is divided by α-glucosidase into fructose and glucose, which are considered to raise plasma uric acid concentration through purine degradation and/or decreased uric acid excretion. Aims: We investigated the effect of acarbose, an α-glucosidase inhibitor, on the increased plasma concentration of uric acid caused by sucrose. Methods: 6 healthy males were studied. After an overnight fast, sucrose at 1.5 g/kg was ingested. Urine was collected 1 hour before sucrose ingestion and then twice at 1-hour intervals after ingestion. Blood was taken twice, at the midpoint of each 1-hour period. 2 weeks later, the same protocol was followed, with acarbose at 100 mg added at the beginning of the sucrose ingestion. Results: Sucrose ingestion raised the plasma concentration of uric acid by 10%, whereas with the addition of acarbose the rise in plasma concentration of uric acid was reduced (p < 0.01) without changes in urinary uric acid excretion and fractional uric acid clearance. Urinary excretion and fractional clearance of oxypurines were unchanged in both experiments. Conclusions: Acarbose is considered to alleviate the rise in plasma concentration of uric acid induced by sucrose by inhibiting its absorption since no changes in uric acid excretion and fractional clearance were observed.Correspondence to:
Y. Moriwaki, MD; Hyogo College of Medicine, Mukogawa-cho 1-1, Nishinomiya, Hyogo, 663-8501, Japan
Email: moriwaki@hyo-med.ac.jp
Adverse Drug Reactions
eptic shock and community-acquired pneumonia associated with etanercept therapy
Abstract
C. Nuñez-Cornejo, J. Borrás-Blasco, A. Gracia-Perez, J.D. Rosique-Robles, V. Lopez-Camps, E. Casterá and F.J. Abad
1Rehabilitation Section, 2Pharmacy Service and 3Intensive Care Unit, Hospital de Sagunto, Sagunto (Valencia), Spain
Objective: To report a case of septic shock and community-acquired pneumonia in a patient with psoriatic arthritis receiving treatment with etanercept. Patient details: A 65-year-old woman diagnosed as having psoriatic arthritis had received treatment with etanercept. Chest X-ray studies were normal and the tuberculin skin test was negative. Two months after etanercept therapy, the patient presented to our emergency department with fever, cough, chest pain and generalized weakness. Chest radiography revealed a right pulmonary infiltrate. Her condition rapidly deteriorated and she went into shock with a further drop in her blood pressure, tachycardia and tachypnea. She was intubated, mechanically ventilated and was treated with fluids, cardioversion and amiodarone. Empiric therapy with levofloxacin, amikacin and cefepime were initiated. In the urinalysis, the result of a rapid test for Streptococcus pneumoniae was positive. Etanercept treatment was suspended due to a possible adverse reaction associated with this drug. At the start of therapy her clinical condition improved slowly. On Day 28, the patient was afebrile and she was discharged from the intensive care unit. Discussion: Most of the infections associated with etanercept therapy have been reported in patients with rheumatoid arthritis. Based on our observations, etanercept was the possible offender in the development of septic shock and respiratory failure in community-acquired pneumonia. There was a temporal relationship between exposure to the drug and onset of symptoms. Etanercept was the only drug administered before the septic shock developed. Based on the Naranjo algorithm, the adverse reaction could be considered possible. Conclusion: Patients initiated on etanercept should be counseled and receive appropriate screening before drug initiation. All febrile and newly occurring concomitant illnesses should be promptly evaluated. General practitioners should discontinue etanercept treatment and institute prompt and aggressive intervention if infection develops.Correspondence to:
J. Borrás-Blasco, PharmD, PhD; Pharmacy Department, Hospital de Sagunto, Avda Ramon y Cajal s/n, Sagunto 46520 (Valencia), Spain
Email: jborrasb@sefh.es
Therapeutics
Use of fondaparinux as an anticoagulant during hemodialysis: a preliminary study
Abstract
K.I. Sombolos, T.K. Fragia, L.C. Gionanlis, P.E. Veneti, G.I. Bamichas, S.K. Fragidis, I.E. Georgoulis and T.A. Natse
1Renal Unit, 2Hematology Laboratory, G.H. “G. Papanikolaou”, Thessaloniki, Greece
Objective: To study the effect of fondaparinux, a new antithrombotic agent, as an anticoagulant during a 4-hour conventional hemodialysis session. Materials and methods: Fondaparinux was administered as an anticoagulant to 16 chronic hemodialysis patients during a single 4-hour hemodialysis session at an intravenous bolus dose of 2.5 mg. Eight patients were using high-flux polyester polymer alloy (PEPA) dialyzers (Group A) and the remainder low-flux polysulfone dialyzers (Group B), whilst all had received conventional doses of tinzaparin sodium as an anticoagulant during the previous month. The dialyzers were primed with 1 l of normal saline containing 5,000 IU of unfractionated heparin. Blood samples for the measurement of INR, APTT (activated partial thromboplastin time) and anti-Xa levels were taken before the study dialysis session (pre), 5 min postdialysis (post), and before the next dialysis session (next). Mean fibrin/clot formation in the extracorporeal circuit and dialyzer was assessed macroscopically by visual inspection and was graded using a 4-point scale. Results: Predialysis anti-Xa levels were 0.04 ± 0.03 IU/ml in Group A, and 0.025 ± 0.025 IU/ml in Group B (p = NS). Postdialysis anti-Xa levels were significantly higher than predialysis levels in both groups (Group A = 0.16 ± 0.04 IU/ml, Group B = 0.46 ± 0.12 IU/ml, p < 0.02 for both) and significantly higher in Group B compared to Group A (p < 0.025). Anti-Xa levels before the next dialysis session were 0.06 ± 0.04 IU/ml in Group A and 0.25 ± 0.06 IU/ml in Group B (p < 0.0001 between Groups A and B). APTT values were significantly higher in postdialysis than predialysis samples for both groups (higher by 27.0 ± 26.0% in Group A and 24.3 ± 31.9% in Group B). No significant differences were found when comparing APTT values in pre, post and next samples between Groups A and B. No differences were also found between pre, post and next samples for INR values, either within or between groups. Mean fibrin/ clot formation score in the extracorporeal circuit at the end of the study dialysis session was significantly higher in patients of Group A than those of Group B (p < 0.05). Dialysis had to be terminated before the completion of 4 hours in 2 patients of Group A because of the presence of extensive fibrin/clots in the circuit and dialyzer. Conclusions: Our findings indicate that fondaparinux sodium at an intravenous dose of 2.5 mg can be used successfully as an anticoagulant during a 4-hour conventional hemodialysis session in patients dialyzed with low-flux polysulfone dialyzers, but not in those dialyzed with high-flux dialyzers. However, anti-Xa levels in the former patients were still increased before the next dialysis session, potentially exposing the patients to an increased risk of bleeding.Correspondence to:
K. Sombolos, MD; Vas. Olgas 82, Thessaloniki, 54643 Greece
Email: sombolos@hol.gr
Bioavailability Section
A bioequivalence study comparing two formulations of lopinavir/ritonavir capsules
Abstract
S.K. Tippabhotla, N.R. Thudi, R. Raghuvanshi, A.H. Khuroo, S. Gurule, S. Mishra, T. Monif and V.K.C. Lao
1Department of Clinical Pharmacology and Pharmacokinetics,
2Product Development and Research Ranbaxy Laboratories Ltd., Gurgaon, Haryana, India, 3Biovail Contract Research, Toronto, ON, and
4Ranbaxy Pharmaceuticals Canada Inc., Mississauga, ON, Canada
This investigation was carried out to evaluate the bioavailability of a new single fixed-dose combination formulation of lopinavir and ritonavir, relative to reference product, Kaletra® (133.3 mg lopinavir/33.3 mg ritonavir) capsules, manufactured by Abbott Laboratories, Chicago, IL, USA. The bioavailability study was carried out on 72 healthy male and female volunteers who received a single dose of 3 capsules (133.3 mg lopinavir/33.3 mg ritonavir) of the test (T) and the reference (R) products in the fasting state, in a randomized, balanced, 2-way crossover design. After dosing, serial blood samples were collected for a period of 72 hours. Plasma harvested from blood was analyzed for lopinavir and ritonavir by a sensitive and validated simultaneous liquid-chromatographic and mass-spectrometric (LC-MS/MS) assay. Mean oral clearance (Cl/F) values of the FDC were 4.92 and 23.54 l/h for lopinavir and ritonavir, respectively, the maximum plasma concentrations (Cmax), area under the plasma concentration-time curve up to the last measurable concentration (AUC0-t), and to infinity (AUC0-¥), were analyzed statistically under the assumption of a multiplicative model. The time to maximum concentration (tmax) was analyzed assuming an additive model. The parametric confidence intervals (90%) were calculated by Schuirmann’s two 1-sided t-test criteria. It was found that the test/reference (T/R) ratios for the pharmacokinetic parameters AUC0-t, AUC0-¥ and Cmax (after initial log transformation) were well within the bioequivalence acceptance range of 80 – 125% as per international regulatory guidelines. Therefore, the two formulations were considered to be bioequivalent [Food and Drug Administration 2003].Correspondence to:
T. Monif, PhD; Vice President, Department of Clinical Pharmacology and Pharmacokinetics, Ranbaxy Laboratories Ltd., Plot No. 20, Sector-18, Udyog Vihar Industrial Area, Gurgaon, 122 015, Haryana, India
Email: tausif.monif@ranbaxy.com
