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Pharmacodynamics

Interpretation of absorption rate data for inhaled fluticasone propionate obtained in compartmental pharmacokinetic modeling

S. Krishnaswami, G. Hochhaus, H. Möllmann, J. Barth and H. Derendorf

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Volume 43 p. 117 - 122

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]

Pharmacokinetics

Population pharmacokinetics of methylprednisolone in accident victims with spinal cord injury

J. Barth, J. Winkler, R. Schumann, N.V. Nagaraja, R. Madabushi, S. Balbach, H. Derendorf, H. Möllmann and G. Möllenhoff

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Volume 42 p. 504 - 511

Abstract

J. Barth¹,², J. Winkler³, R. Schumann², N.V. Nagaraja³, R. Madabushi³, S. Balbach³, H. Derendorf³, H. Möllmann² and G. Möllenhoff²

¹Medical Clinic Bergmannstrost, Halle, ²Medical Clinic Bergmannsheil,
University of Bochum, Germany, and ³Department of Pharmaceutics,
University of Florida, Gainesville, FL, USA
Objective: High-dose methylprednisolone (MP) is used to treat acute spinal cord injury (ASCI). The objective of the present study was to determine the pharmacokinetics of the pro-drug methylprednisolone hemisuccinate (MPHS) and MP in accident victims with ASCI. Methods: The patients (n = 26) were treated with a bolus intravenous loading dose of 30 mg/kg MPHS within 2 h after injury and this was followed by a maintenance infusion of 5.4 mg/kg/h up to 24 h. Blood, CSF and saliva samples were collected up to 48 h after the initial dose and the samples were analyzed by HPLC. Concentration-time data of MPHS and MP were analyzed using population pharmacokinetic analysis with NONMEM software. Results: MPHS and MP could be monitored in plasma and CSF. MP but not MPHS was present in saliva. High variability was seen in the MPHS levels in CSF. The pharmacokinetics of the pro-drug and the metabolite were adequately described by a 2-compartment model with exponential distribution models assigned to the interindividual and the residual variability. At steady state, the average measured MP concentration in plasma was 12.3 ± 7.0 mg/ml and 1.74 ± 0.85 mg/ml in CSF. The CSF levels of MP could be modeled as a part of the peripheral compartment. Conclusion: This study demonstrated that CSF concentrations of MP were sufficiently high after i.v. administration and reflected the concentrations of unbound drug in plasma. Salivary levels of MP were about 32% of the plasma level and may serve as an easily accessible body fluid for drug level monitoring.
Correspondence to:
PD Dr. J. Barth
BG-Kliniken Bergmannstrost
Merseburger Straße 165
D-06112 Halle/Saale, Germany
Email: [email protected]

Talip Study

Comparison of talinolol and atenolol effects on blood pressure in relation to lipid and glucose metabolic parameters. Results from the TALIP study

H. Sourgens, J. Schmidt and H. Derendorf

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Volume 41 p. 22 - 29

Abstract

H. Sourgens, J. Schmidt and H. Derendorf

¹Independent Consultant, Munich, ²Applied Pharmacology, Dresden, Germany, and ³College of Pharmacy, University of Florida, Gainesville, FL, USA
Aims: The primary objective of this double-blind, randomized, parallel-group study was to compare the influence of the selective b₁-receptor antagonists talinolol (100 mg) and atenolol (50 mg) on the lipid metabolism in hyperlipemic patients with mild to moderate hypertension after 12 weeks of treatment. As a secondary endpoint, the influence of the drug on blood pressure, pulse rate as well as glucose metabolism were examined. Furthermore, pharmacokinetic parameters were assessed. Patients: Of the 198 patients recruited for the study, 166 were randomized to receive atenolol (n = 83) or talinolol (n = 83) for up to 12 weeks, 149 patients received the study medication for up to 48 weeks under double-blind conditions. Results: There was no difference between the antihypertensive effect of both b1-selective antagonists in patients with mild to moderate hypertension. No clinically relevant differences between the 2 drugs were observed for LDL cholesterol, HDL cholesterol, total cholesterol and triglycerides in the rather low doses given. However, there was evidence for a decrease in LDL cholesterol following treatment with talinolol, but not following treatment with atenolol, in patients with the highest initial blood pressure and in those with normalized blood pressure after 12 weeks of treatment. Parameters of glucose metabolism were not adversely affected by both drugs. Stable pharmacokinetics were observed over the 12-week administration, and steady state conditions were achieved after a 1-week treatment with both active compounds in the target population. Data indicate that once-a-day dosing can be performed with less fluctuation between peak and trough for talinolol in comparison to atenolol. Both treatments were well tolerated.

Reviews

A review of the effects of chronic exercise and physical fitness level on resting pharmacokinetics

A.M. Persky, N.D. Eddington and H. Derendorf

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Volume 41 p. 504 - 516

Abstract

A.M. Persky, N.D. Eddington and H. Derendorf

¹Department of Pharmaceutics, College of Pharmacy, University of Florida, J.H.M.H.C., Gainesville, Florida, and ²Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA
Pharmacological intervention in cooperation with physical activity is currently being used in the prevention and treatment of diseases like cardiovascular disease and obesity. Physical activity, both acute and chronic, can cause changes in physiology that can alter the observed pharmacokinetics of drugs. Objective: The purpose of this paper is to focus on how chronic exercise can change pharmacokinetics. Results: Chronic exercise can affect drug absorption by the increase in collateral blood flow and absorption may also be affected by changes in gastrointestinal transit times. Chronic exercise may affect volume of distribution of drugs by the increases in lean body mass, decreased fat mass, increased plasma protein and increased plasma volume that occurs with physical conditioning. Changes in hepatic clearance of drugs may explain the differences in systemic clearance seen when comparing physically trained subjects to sedentary ones. Some studies have shown that hepatic enzymes are increased with training but other studies have found no change or lower activities. Finally, renal elimination of drugs may be altered by changes in protein binding but there is little evidence that renal elimination of drugs changes with long-term exercise. Conclusion: Therefore, changes in pharmacokinetics associated with chronic exercise can differ from those during acute exercise and in sedentary subjects. The differences between the physically active and sedentary individuals may require individualization of dosing regimens. It should be noted that there are no standardized protocols to evaluate the influence of exercise on drug disposition.

Population Pharmacokinetics

Estimation of lithium clearance from routine clinical data in Egyptian bipolar patients. A population pharmacokinetic approach

E.S. ELDesoky, V. Kumar, M.S. Alorainy, M.M. Hamdi and H. Derendorf

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Volume 46 p. 617 - 626

Abstract

E.S. ELDesoky¹, V. Kumar², M.S. Alorainy³, M.M. Hamdi¹ and H. Derendorf²

¹Pharmacology Department, Faculty of Medicine, Assiut University, Assiut, Egypt, ²Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, USA, and ³Pharmacology Department, College of Pharmacy, Qasseem University, Saudi Arabia
Population pharmacokinetics (PK) of lithium as a mood stabilizer was investigated in Egyptian patients with bipolar affective disorders (n = 50) of whom 31 were suffering from lithium toxicity. The mean (± SD) age and body weight of patients were 33 ± 10 years and 67 ± 3.6 kg, respectively. Patients selected were maintained on lithium carbonate controlled release tablets at doses of 400 mg/12 hours (n = 43) or 200 mg/12 hours (n = 7) respectively. In 19 patients who continued lithium therapy, 1 blood sample/patient was withdrawn for lithium level determination before the morning dose of the drug was given while for 31 patients who suffered from lithium-related toxicity and cessation of drug intake was therapeutically decided, a single blood was drawn at variable time (36, 48 or 72 h) following the last administered dose of the drug. The data was subjected to population PK analysis using NONMEM and a two-compartment model was used. Due to single point sparse data, not all parameters and their between subject variability (BSV) could be determined. Therefore, lithium clearance (CL) and BSV were estimated while other PK parameters were fixed using available literature information. First order (FO) estimation method was used in the analysis. Covariates were evaluated by univariate analysis using likelihood ratio test. The most significant covariate on lithium CL was found to be creatinine clearance (CrCL). The population CL of lithium in the final model was expressed as CL_pop = 0.51 × (CrCL/105.3)^0.44. The final population PK parameters estimates of lithium were: CL = 0.51 l/h with 12.7% BSV, V₁ (Fixed) = 15.2 l, Q (Fixed) = 7.44 l/h, and V₂ (Fixed) = 6.7 l. The mean value of lithium concentration at 12 hours as predicted by the final model in the patients with drug toxicity was 1.3 ± 0.1 mmol/l versus 0.8 ± 0.14 mmol/l in patients without toxic signs. External validation of the final model on another group of adult bipolar patients (n = 12) maintained on lithium therapy showed a predictive ability of –35 to 65% as represented by% error for the predictions.Correspondence to:
Prof. Dr. E.S. ELDeskoy; Pharmacology Department, Faculty of Medicine, Assiut University, Assiut, Egypt
Email: [email protected]

Original

Population pharmacokinetics of digoxin in Korean patients

N.V. Nagaraja, Y.J. Park, S. Jeon, C.D. Sands and H. Derendorf

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Volume 38 p. 291 - 297

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