Volume 42, No. 1/2004(January)
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 Int. Journal of Clinical Pharmacology and Therapeutics
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Review
Review of NMDA antagonist-induced neurotoxicity and implications for clinical development
Abstract
S.J. Low and C.L. Roland
Cognetix, Inc., Salt Lake City, Utah, USA
NMDA receptor antagonists have been investigated for many years as therapeutic agents for the treatment of neurological disorders such as stroke, epilepsy, pain and Parkinson’s disease. It has been discovered, however, that many of these compounds cause adverse behavioral (psychotomimetic) effects and can produce neurotoxicity characterized by neuronal vacuolization, induction of heat-shock protein, neuronal/axonal degeneration and regional brain cell death in several animal species. It is unknown whether NMDA antagonists induce neurotoxicity in humans. The mechanism of NMDA antagonist-induced neurotoxicity is not completely known, but some evidence suggests disinhibition of GABAergic inputs to the affected neurons. Several classes of compounds have been shown to prevent NMDA antagonist-induced neurotoxicity. The extent of neurotoxicity produced by NMDA antagonists is affected by many factors, including type of antagonist, dose, length of exposure, age, sex and species. While there are no published regulatory guidelines regarding how NMDA antagonist compounds should be evaluated, sponsors and investigators of these compounds should make every effort to assess the potential for neurotoxicity. NMDA receptor antagonists, as well as other CNS-active compounds need to be analyzed for neurotoxicity through careful experimental design, adequate tissue sampling and through the use of a sensitive method of detection.
Pharmacokinetic modeling
Programming of a flexible computer simulation to visualize pharmacokinetic-pharmacodynamic models
Abstract
J. Lötsch1, G. Kobal2 and G. Geisslinger1
1Pharmazentrum Frankfurt, Institute of Clinical Pharmacology, Johann Wolfgang Goethe University, Frankfurt, and
2Institute of Pharmacology, University of Erlangen-Nürnberg, Erlangen, Germany
Teaching pharmacokinetic-pharmacodynamic (PK/PD) models can be made more effective using computer simulations. We propose the programming of educational PK or PK/PD computer simulations as an alternative to the use of pre-built simulation software. This approach has the advantage of adaptability to non-standard or complicated PK or PK/PD models. Simplicity of the programming procedure was achieved by selecting the LabVIEW programming environment. An intuitive user interface to visualize the time courses of drug concentrations or effects can be obtained with pre-built elements. The environment uses a wiring analogy that resembles electrical circuit diagrams rather than abstract programming code. The goal of high interactivity of the simulation was attained by allowing the program to run in continuously repeating loops. This makes the program behave flexibly to the user input. The programming is described with the aid of a 2-compartment PK simulation. Examples of more sophisticated simulation programs are also given where the PK/PD simulation shows drug input, concentrations in plasma, and at effect site and the effects themselves as a function of time. A multi-compartmental model of morphine, including metabolite kinetics and effects is also included. The programs are available for download from the World Wide Web at http:// www.klinik.uni-frankfurt.de/zpharm/klin/ PKPDsimulation/content.html. For pharmacokineticists who only program occasionally, there is the possibility of building the computer simulation, together with the flexible interactive simulation algorithm for clinical pharmacological teaching in the field of PK/PD models.
Pharmacokinetics/Interactions
Pharmacokinetics of moxifloxacin are not influenced by a 7-day pretreatment with 200 mg oral itraconazole given once a day in healthy subjects
Abstract
H. Staß, J. Nagelschmitz, J.-G. Moeller and H. Delesen
Clinical Pharmacology, Bayer AG, Wuppertal, Germany
Aim: The primary objective of this interaction study was to confirm preclinical data suggesting that moxifloxacin is not metabolized by CYP 450 isozymes. Itraconazole, a strong CYP 3A4 inhibitor, was used as comedication. Methods: Twelve healthy male subjects were enrolled in this randomized study using 400 mg of oral moxifloxacin (MXF) administered alone and on the 7th day of a 9-day treatment regimen with itraconazole (ITR) 200 mg p.o., o.d. In addition to the assessment of safety and tolerability, non-compartmental pharmacokinetics of moxifloxacin, itraconazole and their respective metabolites were analyzed using plasma concentrations obtained using HPLC. Results: All treatment regimens were safe and well-tolerated. No interaction with itraconazole was observed for moxifloxacin (relative bioavailability: 111.6% (90% CI 106.5 to 117.0%), Cmax ratio: 103.7% (84.8 – 126.9%) and its sulfometabolite (M1) (AUC ratio: 107.7% (95.6, 121.4%), Cmax ratio: 105.8% (89.9 – 124.5%)). There was a 30% decrease in AUC with M2 moxifloxacin metabolite (glucuronide) accompanied by an approximately 54% increase in renal excretion, which may be due to changes in phase 2 metabolism and/or transport mechanisms altered by itraconazole. Exposure (AUC) to itraconazole and its hydroxymetabolite were marginally altered by moxifloxacin (AUC +5% for itraconazole and –5% for hydroxy-itraconazole (OH-ITR)) indicating the absence of a clinically relevant influence of moxifloxacin on itraconazole. Mean peak concentrations in plasma (Cmax) were reduced for ITR and OH-ITR by approximately 14% and 18%, respectively, when administered concomitantly with moxifloxacin. This was attributed to the sensitivity of itraconazole absorption to changes in gastric physiology (pH, gastric transit, administration after fasting) and was deemed as clinically irrelevant. Conclusion: Results of this study indicate that moxifloxacin is not a substrate for CYP 450 3A4 isozymes confirming previous preclinical in vitro data. Moxifloxacin can therefore be safely coadministered with CYP 3A4 inhibitors without the need for dose adjustment. No clinically relevant changes in the pharmacokinetics of itraconazole were observed during the study.
Pharmacokinetics/Interactions
Effects of recombinant growth hormone therapy on thyroid hormone concentrations
Abstract
B. Kalina-Faska, M. Kalina and B. Koehler
Department of Pediatric Endocrinology and Diabetes, Medical University of Silesia, Katowice, Poland
Background and objective: There are numerous, often contradictory reports on the effects of growth hormone (GH) therapy on thyroid function. The aim of this study was to assess the effect of such therapy on serum concentrations of thyroid hormones in GH-deficient children euthyroid prior to the treatment, and to determine the necessity of thyroid hormone administration in these patients. Material and methods: The study included 32 GH-deficient patients in the first stage of sexual development, in whom disorders of thyroid function could be excluded. The inclusion criteria were based on clinical examination and levels of thyroxine (T4), triiodothyronine (T3), free thyroxine (fT4), free triiodothyronine (fT3), reverse triiodothyronine (rT3), thyrotropin (TSH) before and after stimulation with thyrotropin-releasing hormone (TRH). Recombinant growth hormone (rGH) (Genotropin 16U, Pharmacia) was administered at a dose of 0.7 U/kg/week. Fasting blood samples were drawn before treatment and after 3, 6, 9 and 12 months of therapy. Thyroid hormones were measured using RIA and IRMA methods. Results: There were no physical signs of hypothyroidism in the patients examined during 12 months of rGH administration, and the satisfactory growth rate was achieved. T4 levels decreased in the first 3 months but remained within the normal range, and then returned to the values prior to the treatment. A similar trend was observed for fT4, with 28.5% of patients exhibiting fT4 levels below the normal in the 3rd month. An increase during the first 3 months of therapy was observed in the cases of T3 (statistically non-significant) and fT3, and these values then fell to levels within the normal range of patients’ age. During treatment, TSH levels decreased but remained within the normal range. Conclusions: A transient decrease in T4 concentrations in the 3rd month with unchanged T3 and an increase in fT3 concentrations probably result from the effect of rGH on the peripheral metabolism of thyroid hormones. The results obtained do not support the use of thyroid hormone therapy with levothyroxine during the first year of rGH therapy in patients who are initially euthyroid.
Antibiotic Therapy
Presurgical antimicrobial prophylaxis: effect on ocular flora in healthy patients
Abstract
G. Chisari, G. Cavallaro, M. Reibaldi and S. Biondi
1Center for Ocular Microbiology, 2Department of Medicine and Surgery, Ophthalmology Section, University of Catania, and
3Department of Otolaryngology and Ophthalmology, University of Bari, Italy
Objective: Evaluation of presurgical antimicrobial prophylaxis for reduction of ocular flora. Setting: Ophthalmology Section, Department of Medicine and Surgery, University of Catania, Italy. Methods: Three days before photorefractive keratectomy (PRK), conjunctiva of 70 healthy patients (100 eyes) were swabbed. After 3 days of instillation of ofloxacin 0.3% (3 times daily), conjunctival swabs were taken again. Bacteria were isolated and identified from each swab. Results: A total of 191 independent isolates were obtained prior to antimicrobial treatment. Bacteria were isolated from all 100 eyes sampled. Gram-positive species predominated, with Staphylococcus epidermidis and Staphylococcus aureus cultured from 69% and 25% of eyes sampled, respectively. Species of the anaerobic genera Peptococcus and Peptostreptococcus were found in 22% and 14% of eyes, respectively. After prophylaxis with ofloxacin, bacteria could be cultured from only 7% of eyes (10 independent isolates). All isolates were sensitive to ofloxacin except 5 strains of S. epidermidis, which displayed intermediate sensitivity. No infections occurred after PRK. Conclusion: Prophylaxis by instillation of ofloxacin 0.3% 3 times daily for 3 days substantially reduced the ocular flora of 100 healthy eyes prior to refractive surgery.
Bioavailability Section
Bioequivalence study of two fluconazole capsule formulations in healthy volunteers
Abstract
R. Pereira1, S. Fidelis1, M.L.P. Vanunci1, C.H. Oliveira2, G.D. Mendes3, E. Abib1 and R.A. Moreno1,4
1Synchrophar Assessoria e Desenvolvimento de Projetos Clínicos, Campinas, 2Nautillus Clinic and Biologic Attendance, Hortolandia, 3Cartesius Analytical Unit, Department of Pharmacology, ICB-University of São Paulo, and 4Department of Physiology, Faculty of Americana, Americana, Brazil
Objective: To compare the bioavailability of a fluconazole 150 mg capsule formulation from Laboratório Teuto Brasileiro Ltd., Brazil (test formulation), and Zoltec 150 mg capsule from Laboratórios Pfizer Ltd., Brazil (reference formulation), in 24 volunteers of both sexes. Material and methods: The study was conducted open with randomized 2-period crossover design and a 2-week washout period. Plasma samples were obtained over a 168-hour interval. Fluconazole concentrations were analyzed by combined reversed-phase liquid chromatography and tandem mass spectrometry (LC/MS/MS) with positive ion electrospray ionization using selected ion monitoring method. From the fluconazole plasma concentration vs. time curves the following pharmacokinetic parameters were obtained: AUClast, AUC0-inf and Cmax. Results: Geometric mean of fluconazole/Zoltec 150 mg individual percent ratio was 102.6% for AUClast, 102.2% for AUC0-inf and 109.4% for Cmax. The 90% confidence intervals were 97.3 – 108.2%, 97.0 – 107.8%, and 103.1 – 116.0%, respectively. Conclusion: Since the 90% CI for both Cmax, AUClast and AUC0-inf were within the 80 – 125% interval proposed by the Food and Drug Administration, it was concluded that fluconazole 150 mg capsule was bioequivalent to Zoltec 150 mg, according to both the rate and extent of absorption.
Bioavailability Section
Phentolamine bioequivalence study
Abstract
L.F.G. Silva1, M.O. Moraes2, G.S.M. Santana2, F.A. Frota Bezerra2, G. De Nucci3 and M.E.A. Moraes2
1Urology, 2Clinical Pharmacology, Clinical Pharmacology Unit (UNIFAC),
Federal University of Ceara, and 3Clinical Pharmacology,
State University of Sao Paulo, Brazil
Objective: To assess the bioequivalence of 2 tablet formulations of phentolamine (Regitine phentolamine 40 mg tablet formulation by Novartis, Brazil, as test formulation, and Vasomax, phentolamine 40 mg tablet formulation by Schering Plough S.A., Brazil, as reference formulation). Methods: A single 40 mg oral dose of each formulation was administered to 36 male healthy volunteers. The study was conducted after screening, using an open, randomized, 2-period crossover design, a 7-day interval between doses, and wash-out period of at least 4 weeks. Plasma samples for determination of phentolamine were obtained predose and at intervals over 720 min postdose. Plasma concentrations were quantified by reversed-phase liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM) method. Precision of the method was evaluated using calibration curves and plasma quality control samples. The subjects were monitored throughout the study. Systolic and diastolic blood pressure and pulse rate measurement were taken predose and at intervals up to 720 min. Tolerance of both products was good. No serious adverse reactions were reported. The pharmacokinetic parameters calculated for both compounds included: AUC(0-720 min), AUC(0-¥), Cmax, Cmax/AUC(0-720 min), tmax, t1/2 and ke. Results: The maximum concentrations reached (Cmax) were compared. Regitine 40 mg formulation Cmax geometric mean ratio was 108.29% (90% CI = 98.58 – 118.96) of Vasomax 40 mg formulation. The areas under the curve (AUC(0-720 min)) were compared. Regitine 40 formulation (AUC(0-720 min) geometric mean ratio was 102.33% (90% CI = 97.21 – 107.72) of Vasomax 40 mg formulation. Conclusion: Since the 90% CI for both Cmax and AUC ratio where inside the 80 to 125% interval proposed by the Food and Drug Administration, it is concluded that Regitine 40 mg tablet is bioequivalent to Vasomax for the rate and extent of absorption.
Bioavailability Section
Bioequivalence study comparing a new paracetamol solution for injection and propacetamol after single intravenous infusion in healthy subjects
Abstract
B. Flouvat1, A. Leneveu1, S. Fitoussi2, B. Delhotal-Landes1 and A. Gendron3
1Laboratoire de Toxicologie, Hôpital Ambroise Paré, 2Therapharm Recherches, Boulogne Billancourt, and 3Medical Department, Bristol-Myers Squibb, Rueil-Malmaison, France
Objectives: A new, ready-to-use solution for injection of paracetamol (Perfalgan® 10 mg/ml) without previous reconstitution has been developed. The aim of the study was to determine the serum concentration profiles of paracetamol after 15 min infusion of Perfalgan® 0.5 g and 1 g doses and to demonstrate the bioequivalence between Perfalgan® 1 g dose and a marketed reference formulation for injection, propacetamol 2 g (Pro-Dafalgan® 2 g) equivalent to 1 g of paracetamol. The secondary objective was to evaluate local tolerance, and clinical and biological safety. Methods: The study was performed in 24 healthy, male volunteers, according to an open-label, randomized, single-dose, 3-period crossover design, with a 1-week washout period between the doses. Blood samples were taken prior to each administration and at 18 time points within the 24-hour period following the beginning of each infusion. Serum concentrations of paracetamol were determined by validated high-performance liquid chromatography with UV detection. From serum concentration-time data, a non-compartmental pharmacokinetic analysis was performed to calculate Cmax, tmax, AUC(inf), t1/2, MRT, ClT and Vd. Log-transformed AUC(inf) and Cmax were tested for bioequivalence. The local pain intensity at infusion site was assessed using a 4-point categorical scale from 0 (none) to 3 (severe). The clinical and biological safety was evaluated by physical examination with measurements of vital signs and ECG and laboratory tests including hematology and biochemistry. Results: After infusion of 0.5 g and 1 g of the new paracetamol solution, Cmax and AUC(inf) increased proportionally with dosage. After dose correction to 1 g of paracetamol, the mean (± SD) Cmax ratio was 0.98 ± 0.24 and 0.94 ± 0.08 for AUC ratio. Identical tmax was observed for the 2 paracetamol dosages and 90% confidence intervals for t1/2, MRT, ClT and Vd were within the acceptable interval 0.8 – 1.25. The calculated 90% confidence intervals of the new solution (Perfalgan® 1 g) to marketed solution (propacetamol 2 g) ratios were 1.11 – 1.31 (point estimate 1.20) for Cmax and 1.10 – 1.16 (point estimate 1.13) for AUC(inf). These values were within the acceptable bioequivalence intervals of 0.75 to 1.33 for Cmax and 0.80 – 1.25 for AUC(inf). Application site disorders were the most frequently observed adverse events but local pain at infusion site was less reported by subjects after Perfalgan® (2%) compared to propacetamol (20%). The clinical and biological safety was good and equivalent for the 3 treatments. Conclusion: After administration of paracetamol solution for injection 0.5 g and 1 g, the pharmacokinetics of paracetamol is linear. All results indicate that 1 g of paracetamol administered as Perfalgan® 10 mg/ml is bioequivalent to propacetamol 2 g with a better local safety.
Bioavailability Section
Reproducibility of nifedipine absorption from GITS tablets: comparison of single-dose pharmacokinetics using 10, 20, 40 and 60 mg nifedipine
Abstract
T. Tateishi1, K. Okumura2, Y. Orii2 and T. Tanaka2
1Department of Clinical Pharmacology, Hirosaki University School of Medicine, Hirosaki, and 2Bayer Yakuhin Ltd., Osaka, Japan
Objective: To examine the reproducibility of nifedipine absorption from gastrointestinal therapeutic system (GITS) tablets by comparing the single-dose pharmacokinetic profiles of 4 different dosages administered orally. Methods: Twelve healthy male volunteers, aged between 22 and 29 years were enrolled in the open, 4-way, dose escalation study with single oral doses of 10, 20, 40 and 60 mg (two 30 mg) nifedipine GITS tablets. Each administration was separated by a 1-week washout period. Coefficients of variation (CV) of dose-corrected area under the concentration-time curve (AUC) and peak plasma drug concentrations (Cmax) were calculated from the pharmacokinetic profiles. Results: Mean AUC and mean Cmax were dose-proportional from 10 to 60 mg. Although the CV of 4 mean dose-corrected AUC and Cmax were 5.5% and 17.5%, respectively, CV of dose-corrected AUC and Cmax in each subject varied from 5.1 to 37.4% (mean 11.0%) and from 14.1% to 46.4% (mean 25.8%), respectively. Conclusions: Whereas mean plasma nifedipine concentration remained markedly stable over a 16- to 24-hour interval and mean dose-corrected AUC showed good reproducibility with nifedipine GITS, the CV of dose-corrected AUC of the nifedipine GITS tablets in each subject showed large variability.
