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Abstract

Z.R. Tayab¹, G. Hochhaus¹, S. Kaufmann², D. Jäger² and J. Barth²

¹Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA, and ²Clinics of the Berufsgenossenschaft Bergmannstrost, Halle, Germany
Objective: In general, the pharmacokinetics (PK) of antibiotics in intensive care unit (ICU) patients are known to differ from healthy subjects. These differences can pose challenges in developing appropriate dosing guidelines. The primary objective of this report was to characterize the disposition of levofloxacin in critically ill patients and to assess any relationships between patient covariates and the PK parameters. Methods: 20 patients in the ICU were given levofloxacin, 500 mg, as an i.v. infusion for a half hour. Plasma samples were taken until 24 hours and assayed using HPLC. The concentration-time data were analyzed using population analysis with NONMEM. Results: The data were described using a 2-compartment model. Creatinine clearance was determined to be a statistically significant predictor of variability in total levofloxacin clearance. For patients with higher levofloxacin clearance, the resulting efficacy for different strains of bacteria (expressed as free AUC/MIC ratios) suggested that for less sensitive pathogens, a dosage adjustment may be needed. Conclusion: A model describing the pharmacokinetics of levofloxacin in critically ill patients was developed. It was determined that creatinine clearance has a significant role in the disposition of levofloxacin. This may have significant implications in the clinical setting for identifying optimal dosage regimens for ICU patients.Correspondence to:
G. Hochhaus, PhD
P.O. Box 100494
Department of Pharmaceutics
College of Pharmacy, JHMHC
University of Florida
Gainesville, FL 32610, USA
Email: [email protected]

Abstract

S. Krishnaswami¹,², G. Hochhaus¹, H. Möllmann³, J. Barth⁴ and H. Derendorf¹

¹Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, ²Pfizer Global R&D, Ann Arbor, MI, USA,
³University of Bochum and ⁴Clinic Bergmannstrost, Halle, Germany
Objective: Reports characterizing the pharmacokinetics of inhaled fluticasone propionate (FP) using compartmental approaches have suggested that the absorption of FP into the systemic circulation is rapid with a half-life of approximately 10 min. We believe that this is a classical case of misassignment of the pharmacokinetic parameter estimates, a problem often encountered while modeling pharmacokinetic data. The objective of this study was to illustrate and analyze this problem using actual blood level data of FP obtained in 14 healthy subjects. Materials and methods: Serum concentration-time data of FP were obtained from a double-blind, randomized study involving single and multiple twice-daily inhalations of 500 mg via a dry powder device, Diskus®. The profiles were fitted using one- and two-compartment pharmacokinetic models with first order absorption. Various permutations of the resulting exponential rate constants were analyzed to determine the combination that was most consistent with the underlying physical process. Results: The two-compartment body model with first order absorption gave excellent fits for the observed FP concentrations after both single and multiple dosing. Even though peak levels were reached relatively early (30 – 90 min) after inhalation, the combination that most appropriately described the underlying process was a > Ka > b, i.e. slow absorption, rapid distribution and slower elimination kinetics. The absorption, distribution and elimination half-lives resulted to be 3.8 h, 9.9 min and 13.6 h, respectively, consistent with the high lipophilicity and sustained dissolution characteristics observed in vitro. Conclusions: Analysis of FP pharmacokinetics after inhalation represents a classical case of potential misassignment of the exponential rate constants, which if ignored, could lead to erroneous interpretations regarding the underlying process. The study also elucidates the pitfall of using tmax to calculate absorption rate.Correspondence to:
H. Derendorf, Ph.D
P.O.Box 100494
Dept. of Pharmaceutics,
College of Pharmacy
University of Florida
Gainesville, FL 32610-0494, USA
Email: [email protected]

Abstract

K. Raith and G. Hochhaus

Department of Pharmaceutics, School of Pharmacy, University of Florida, JHMHSC, Gainesville, FL, USA
Opioid drugs used in the treatment of severe pain are known to produce tolerance that requires a dose increase to maintain a sufficient analgesic effect. As this is connected with side effects such as respiratory depression, it is highly desirable to avoid or at least attenuate the development of tolerance. Closely related, but in some respect dissociable, is the phenomenon of physical dependence, which becomes apparent particularly in heroin withdrawal. Our knowledge about the mechanisms underlying tolerance has increased dramatically in recent years, but a final picture of the importance of each particular mechanism under in vivo conditions has not yet emerged. Recent studies suggest that the so-called receptor down-regulation is not the main mechanism in vivo. A desensitization on the basis of receptor decoupling, receptor internalization and increased alternative coupling to stimulatory G-proteins have been demonstrated. However, a functional antagonism of the opioid effects seems to be clinically most important, mediated by the activation of NMDA receptors, up-regulation of adenylyl cyclase and nitric oxide synthase. Drugs blocking these mechanisms are the most promising option in the treatment of tolerance. Namely, a2-adrenoreceptor agonists such as clonidine and NMDA antagonists such as ketamine or dextromethorphan have been used to minimize tolerance development during opioid treatment. Moreover, clinical strategies such as opioid rotation and multimodal analgesia, i.e. the simultaneous application of several analgetics of different type, have proven to be successful approaches.

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