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Abstract

M. Kanamori, H. Takahashi and H. Echizen

Postgraduate School of Clinical Pharmacy, Meiji Pharmaceutical University, Tokyo, Japan
Aims: Body weight- (BW) normalized pediatric dosages of metabolically eliminated drugs often exceed the corresponding adult values. We aimed to clarify whether such findings would be attributable either to an augmented hepatic drug-metabolizing activity or to a systematic bias introduced by adopting BW as a size standard of clearance. Materials and methods: We chose 3 model drugs that are metabolized by distinct cytochrome P450 (CYP) isoforms (theophylline, phenytoin and cyclosporine for CYP1A2, CYP2C9/2C19 and CYP3A4, respectively). The MEDLINE database covering 1966 to May 2001, was searched for articles where systemic clearance of theophylline or oral clearance of cyclosporine and Vmax/ Km of phenytoin were reported with demographic data of individual children. Liver weights (LWs) of children were estimated using the equation constructed based upon the autopsy data in literature, and body surface area (BSA) was calculated using a standard formula. Relationships between age and clearance of the 3 model drugs that were normalized against BW, LW and BSA were examined. The analysis was confined to the data obtained from children older than 1 year due to scarcity of data for infants and neonates. Results: Relevant data were obtained from 24, 46 and 14 children for theophylline, phenytoin and cyclosporine, respectively. The development of LW lags behind that of BW but is almost identical to that of BSA. Thus, children had a greater LW/BW ratio than adults. The BW-normalized clearance of theophylline and Vmax/Km of phenytoin showed significantly (p < 0.01) negative correlations with age (r = –0.43 and –0.50, respectively) during childhood, whereas their LW- or BSA-normalized clearances were independent of age. Conclusions: While our analyses were made upon limited numbers of subjects and range of age, the results suggest that children appear to have an augmented BW-normalized clearance for drugs of which metabolism is dominated by the CYP1A2, CYP2C9 or CYP3A4 due mainly to a lagged development of BW than that of LW during childhood. BSA would serve as a practical alternative to LW for scaling adult dosage of metabolically eliminated drugs to children.Correspondence to:
Prof. Dr. H. Echizen; Department of Pharmacotherapy, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 042-0855, Japan
Email: echizen@my-pharm.ac.jp

Abstract

Y. Kakiuchi¹, T. Fukuda², M. Miyabe², M. Homma¹,³, H. Toyooka² and Y. Kohda¹,³

¹Department of Pharmacy, Tsukuba University Hospital, Tsukuba, Ibaraki, Departments of ²Anesthesiology and ³Pharmaceutical Sciences, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
Objective: We developed a simple and selective assay method for simultaneous determination of free lidocaine (LDC) and its active metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX) in plasma, by using high-performance liquid chromatography (HPLC). The method was applied to the plasma concentration monitoring in continuous epidural anesthesia with LDC. Materials and methods: Free fraction was separated from plasma by using an ultrafiltration technique. Free and total LDC, MEGX and GX in plasma were analyzed by HPLC equipped with ordinary octadecylsilyl silica (ODS) column and ultraviolet (UV) detector. Patients: Five male patients with cancer who received epidural injection of 1.5% LDC for 5 hours in elective thoracic surgery, were enrolled to determine the plasma levels of total and free LDC, MEGX and GX. Results and discussion: The calibration curve for free LDC, MEGX and GX were linear at the concentration of 25 to 1,000 ng ml–1 (r = 0.9998 – 0.9999). The recoveries for LDC, MEGX and GX from plasma water were ranged 73.2 – 89.1%. The coefficient variations for intra- and inter-day assay for LDC, MEGX and GX were less than 4.1%. The detection limit of each drug was 20 ng ml–1. Plasma-free MEGX after 180 min epidural injection was higher than free LDC, even though the total concentration of MEGX was 4 times lower than that of LDC. The percentages of free fraction for LDC, MEGX and GX were 11.7, 48.5 and 78.3% after 5-hour epidural administration of LDC. Since the free fraction of MEGX and GX increases and exceeds the concentration of free LDC during continuous epidural anesthesia, accumulation of these toxic metabolites should be carefully monitored as well as LDC. Conclusion: The present method is a reliable technique and can be applied to monitoring free LDC, MEGX and GX, which provide us beneficial information as to the LDC metabolism and toxicity.Correspondence to:
Dr. Y. Kakiuchi; Department of Pharmacy, Tsukuba University Hospital, 2-1-1 Amakubo, Tsukuba, Ibaraki 305-8576, Japan
Email: ykaki@mail.hosp.tsukuba.ac.jp

Abstract

M. Sanaka¹, Y. Kuyama², Y. Shimomura², M. Saitoh² and K. Hattori²

¹Department of Internal Medicine, Tokyo Metropolitan Komagome Hospital, and ²Department of Internal Medicine, School of Medicine, Teikyo University, Tokyo, Japan
Objective: Gastric emptying (GE) of liquids is quantified as the rate of paracetamol absorption in clinical and research settings (paracetamol method). A conventional 1-compartment model assumes the first-order rate kinetics for paracetamol absorption. This assumption seems improper when paracetamol is coingested with a caloric liquid meal, because the caloric liquid leaves the stomach at a constant rate (zero-order process). Theories based on the 1-compartment model reveal that tmax and Cmax/AUC¥ accurately reflect the rate of paracetamol absorption, but whether this is also the case when paracetamol is administered with a caloric liquid, has not been investigated. The aims of this study were to propose a new mathematical model for accurately describing absorptive behaviors of paracetamol added to a caloric liquid meal, and, using the model, to clarify the characteristics of tmax and Cmax/AUC¥ as rate parameters. Methods: Based on the newly developed model, tmax and Cmax/AUC¥ were mathematically expressed in terms of GE rates. Subsequently, the characteristics of tmax and Cmax/AUC¥ were elucidated by simulation works. Results: The simulation study showed that both tmax and Cmax/AUC¥ could reflect GE rates, tmax was a more sensitive index of GE than Cmax/AUC¥, and tmax was less reliable than Cmax/AUC¥ if GE is very rapid. Conclusions: In the paracetamol method using a caloric liquid test meal, tmax and Cmax/AUC¥ are suitable for detecting delayed and rapid GE, respectively.Correspondence to:
Dr. Y. Kuyama; Department of Internal Medicine, School of Medicine, Teikyo University, 2-11-1, Kaga, Itabashi-ku, Tokyo 173, Japan
Email: kuyama@med.teikyo-u.ac.jp

Abstract

J.S. Barrett¹, A.S. Joshi¹, M. Chai¹, T.M. Ludden², W.D. Fiske¹ and H.J. Pieniaszek Jr.¹

¹Drug Metabolism and Pharmacokinetics Department, DuPont Pharmaceuticals, Newark, DE, and ²University of Nebraska, Lincoln, Nebraska, USA
A population-based pharmacokinetic (PK) model has been developed for efavirenz based on 16 phase I studies. The combined data set consisted of 334 healthy volunteers, 2,907 efavirenz dose administrations and 9,342 measured plasma concentrations across a range of doses from 100 – 600 mg. The pharmacokinetic structural model was a 2-compartment model with first-order absorption with differentiation between single- and multiple-dose exposure to account for known hepatic cytochrome P450 induction of efavirenz metabolism. Model-building was performed on the index data set (66% of the total database), as a data-splitting technique was used to validate the final model using NONMEM. The final model confirmed the appropriateness of separate clearance terms for single and multiple dose administration (2.65 versus 10.2 l/h, respectively). Clearance increased with dose and frequency of administration. A lower clearance was predicted in Asians and Blacks relative to Caucasians. A slightly lower clearance was observed in females relative to males (9.08 compared to 10.2 l/h in males) and interactions on clearance due to co-administration of fluconazole, ritonavir, rifampin, indinavir and azithromycin were identified. The magnitudes of these effects were small and did not suggest dose adjustment in the various subpopulations. With little exception, these results agree with the findings from the non-compartmental analyses. The residual variability was 21% CV and the intersubject variation in CL/F and V/F was 48 and 85%, respectively. The phase I meta-analysis was able to substantiate the pharmacokinetic characteristics of efavirenz derived from the composite of individual well-defined studies. The model was deemed adequate for subsequent evaluation in HIV-infected patients. Covariates and outlier classes identified in this phase I meta-analysis were similarly identified in subsequent analyses of patient data.Correspondence to:
Dr. J.S. Barrett; Aventis Pharmaceuticals, Route 202-206, PO Box 6800, Bridgewater, New Jersey 08807, USA
Email: jeff.barrett@aventis.com

Abstract

N. Takami¹, Y. Yamamoto¹, H. Matsuo², H. Ohtani² and Y. Sawada²

¹Chubutokusyukai Hospital, Okinawa, and ²Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
A 70-year-old Japanese woman with renal dysfunction under hemodialysis presented with vomiting and chill with fever. Over the previous 24 weeks she had been taking 75 mg of ranitidine after hemodialysis. Other medications taken were prednisolone, furosemide, a-calcidol, amlodipine and calcium carbonate. Before starting ranitidine, she had been treated with famotidine for about 2 years without complication. Hematological inspection on admission revealed agranulocytosis with WBC of 400/mm3. Ranitidine was discontinued and granulocyte colony-stimulating factor (G-CSF) was started. On Day 3, laboratory data showed slight improvement of cytopenia with WBC of 1,000/mm3. On Day 6, her hemogram showed marked improvement with WBC of 11,700/mm3 and G-CSF was discontinued. She was discharged on Day 10. Several cases describing ranitidine-induced cytopenia are associated with the use of ranitidine at a dose of 150 mg/day or higher, and adverse reactions were found within 2 – 35 days after beginning ranitidine treatment. In the case described here, however, the adverse reaction occurred after a longer treatment period with ranitidine at a lower dose. In conclusion, ranitidine should be administered with great caution to patients with severe renal dysfunction.Correspondence to:
Prof. Dr. Y. Sawada; Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
Email: sawada@phar.kyushu-u.ac.jp

Abstract

G. Flesch¹, D. Tudor², C. Souppart³, J. D’Souza⁴ and M. Hossain⁵

¹Clinical Pharmacology, Novartis Pharma AG, Basel, Switzerland, ²Boomerang Pharmaceutical Communications, Mulhouse, ³DMPK, Novartis Pharma SA, Rueil-Malmaison, France, ⁴Clinical Research, Novartis Pharma AG, and ⁵Clinical Pharmacology, Novartis Pharmaceuticals Corporation, East Hanover, USA
A final market image (FMI) tablet formulation of oxcarbazepine was compared with the marketed formulation (current market formulation (CMF)) and with the clinical trial formulation (CTF) tablet used during clinical efficacy and safety studies. The goal of the study was to compare the bioavailability after single doses and at steady state of the FMI versus CMF and CTF as well. Additionally, the effect of food was evaluated on the final market formulation. The study was an open-label, single-center, 4-way crossover trial. Each treatment period consisted of a single dose of 600 mg OXC on Day 1. From Day 4 up to including Day 7, 600 mg b.i.d. were administered. A final dose of 600 mg was administered in the morning on Day 8. Blood samples were taken on Day 1 before and on Day 7 (predose) and on Day 8 (morning dose). Plasma concentrations of MHD (the main metabolite of OXC) were determined by using a validated HPLC assay. FMI as test formulation was compared with the CMF and CTF as reference formulations. FMI under fed conditions was also compared with FMI under fasting conditions. These comparisons were made using data following single-dose administration and steady state conditions. Plasma AUC for single dose or AUC(0-12h) for steady state, and plasma Cmax, log-transformed (natural base), were used for the assessment of bioequivalence. The 90% confidence interval (CI) approach was used for testing bioequivalence. Bioequivalence was accepted if the CI was contained within the region (0.8, 1.25). At steady state under fed conditions, tested formulation (FMI) was bioequivalent to CTF and with the reference marketed formulation (CMF) with regard to AUC and Cmax. After single dose under fed conditions, FMI and CTF were bioequivalent with regard to AUC and Cmax, and FMI and CMF were equivalent with regard to AUC but not Cmax. Food had no effect on the bioavailability of the FMI. These results clearly support the switch from the current market formulation (CMF) to the final market image tablet in the countries where Trileptal is or was already registered.Correspondence to:
Dr. G. Flesch; Clinical Pharmacology, WSJ-027.7.27, Novartis Limited, CH-4002 Basel, Switzerland
Email: gerard_jp.flesch@pharma.novartis.com

Abstract

N.H. Rietbrock

Abstract

V.K. Grover, R. Mahajan, L.N. Yaddanapudi, H.G. Sudarshana and K.D. Gill

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Volume 40, No. 11/2002(November)