Elizabeth A. Ludwig

Pharmacokinetics and pharmacodynamic modeling of direct suppression effects of methylprednisolone on serum cortisol and blood histamine in human subjects

Pharmacodynamic models for “directly suppressive” effects of methylprednisolone are based on the premise that receptor interactions of steroids are followed by immediate suppression of either the circadian secretion of cortisol or the constant rate recirculation of histamine‐containing basophils that persists until inhibitory concentrations of methylprednisolone disappear. Methylprednisolone doses of 0, 10, 20, and 40 mg were given as the 21‐succinate sodium salt in a balanced crossover study to six normal men. Plasma steroid concentrations and blood histamine were measured simultaneously. Both forms of methylnisolone exhibited linear kinetic parameters. One dynamic model quantitates the baseline circadian pattern and the decline and return of cortisol with similar parameter estimates for all three dose levels. A similar model describes the monoexponential decline and the log‐linear return to steady‐state baseline of blood histamine. Similar inhibitory concentration values for both effects approximated the equilibrium dissociation constant of in vitro steroid receptor binding. The new models are more physiologically appropriate for these steroid effects than three other models that are commonly employed in pharmacodynamics. Steroid effects generally appear to be receptor mediated with either nongene immediate responses or gene‐mediated delayed effects. These models allow quantitation of the rapid effects of steroids with simple equations and common fitted parameters for all steroid dose levels.

Evaluation of dose-related pharmacokinetics and pharmacodynamics of prednisolone in man

The pharmacokinetics and pharmacodynamics of prednisolone were evaluated in normal male volunteers. Seven subjects completed 3 phases: 16.4−and 49.2−mg iv prednisolone, and a phase with no drug to assess baseline responses. Plasma concentrations of prednisolone and urine concentrations of prednisolone and 5 metabolites were assayed by HPLC. Protein binding of prednisolone was measured by ultrafiltration. The polyexponential disposition of free and total plasma prednisolone were evaluated and apparent parameters were compared between doses. Suppression of plasma cortisol and alterations in blood basophil and helper-T cell trafficking were used as pharmacodynamic indices. Pharmacodynamic models were used to relate total or free plasma prednisolone concentrations to each of these effects generating response parameters and IC50(50% inhibitory) concentrations common to both doses. The pharmacokinetics of total drug were comparable to previous findings with CLand Vssincreasing with dose. Free prednisolone exhibited slight capacitylimited elimination and distribution as CLand Vssdecreased with the larger dose. Pharmacodynamic models jointly fitting all three phases characterized the suppression/trafficking phenomena equally well with use of total or free drug concentrations. In each case the models provided realistic values of parameters relating to steroid sensitivity-in particular IC50-and to the underlying physiology of the affected systems. This study comprehensively elucidates the complexities of prednisolone pharmacokinetics and demonstrates how plasma concentration-time profiles of total or free prednisolone can be utilized for evaluation of prednisolone pharmacodynamics.

Oral contraceptive effects on methylprednisolone pharmacokinetics and pharmacodynamics

Oral contraceptive (OC) steroids alter the disposition of numerous drugs, including corticosteroids. We investigated the pharmacokinetics and pharmacodynamics of methylprednisolone.

Pharmacoimmunodynamics of methylprednisolone : trafficking of helper T lymphocytes

A two-compartment dosed model was used to characterize the cell trafficking behavior of helper T cells in response to various single doses of methylprednisolone. Steroids are assumed to inhibit the circadian-determined cell return from extravascular sites to blood in a classic inhibitory pattern reflected by an IC50.The rate of cell efflux from tissues is modeled with a cosine function having a period of 24 hr and a maximum at about 1 am. Nonlinear leastsquares regression employing differential equations was used to analyze helper T-cell data from three human studies from our laboratory. The IC50value of methylprednisolone of 12–19 ng/ml approximates receptor KDvalues. Simulations were performed to demonstrate the log-linear role of steroid dose or AUCon the integral of effect of helper T cells over a wide range of methylprednisolone doses. This pharmacodynamic model allows flexibility for characterizing any type of steroid dosing regimen and is relevent in describing complex response data for corticosteroid immunosuppressive effects in man.

Pharmacokinetics and pharmacodynamics of methylprednisolone when administered at 8 AM versus 4 PM

The temporal variations in the pharmacokinetics and pharmacodynamics of methylprednisolone at 8 AM versus 4 PM were investigated in six healthy male volunteers. Subjects completed three phases: no drug administration, 20 mg intravenous methylprednisolone at 8 AM, and the same dose at 4 PM. Methylprednisolone clearance was 28% greater in the afternoon. The suppressive effects of methylprednisolone on basophils (measured as whole blood histamine), helper T lymphocytes, and cortisol concentrations, assessed by the ratio of the area under the curve (AUC) after methylprednisolone to the baseline AUC, were not different between the phases. The 50% inhibitory concentration values for methylprednisolone derived from pharmacodynamic models were also similar, indicating no difference in intrinsic responsiveness. However, cortisol concentrations returned to baseline about 4 hours earlier after the 4 PM compared with the 8 AM dose because of the enhanced afternoon methylprednisolone clearance. These findings are in agreement with other studies that suggest adequate clinical effects and less disturbance of cortisol circadian behavior when methylprednisolone is administered as a single dose in the morning.

Pharmacodynamic model for joint exogenous and endogenous corticosteroid suppression of lymphocyte trafficking

The circadian pattern of the immune system correlates with that of circulating T-helper cells and inversely with cortisol concentrations. Corticosteroids, both endogenous and exogenous, cause lymphocyte dimunition in blood by retention of cells in the lymphatic circulation. A physiologic pharmacodynamic model was developed to describe changes in circulating lymphocytes as a function of both endogenous cortisol and methylprednisolone concentrations. The model was applied to T-helper and T-suppressor cell data collected from six asthmatic men during baseline, after single-dose, and after 6 days of 20 mg daily methylprednisolone. The model described all phases of the study well. Baseline circadian rhythm of lymphocytes was related to cortisol concentrations. Multiple-dosing of methylprednisolone caused apparent tolerance and decreased the sensitivity of lymphocytes to corticosteroids by 116% and markedly reduced endogenous cortisol concentrations. A 60% increase in circulating T-helper cells was observed which could be accounted for by dual changes in receptor sensitivity and endogenous cortisol.

Steroid-Specific Effects of Ketoconazole on Corticosteroid Disposition: Unaltered Prednisolone Elimination

Ketoconazole inhibits the clearance of methylprednisolone by 60 percent and extends cortisol suppression beyond that produced by methylprednisolone alone. This study examined prednisolone pharmacokinetics and cortisol suppression in four healthy male volunteers following administration of prednisone 20 mg. Studies were performed with and without ketoconazole 200 mg po for six days. Blood samples were obtained serially over 24 hours and serum prednisone, prednisolone, and cortisol concentrations were determined by HPLC. Prednisolone clearance before and after ketoconazole therapy was not significantly different (160 ±38 vs. 148 ±23 mL/h/kg). In addition, no significant differences were found in mean residence time (5.03 ±0.69 vs. 6.18 ±1.77 h), terminal slope (0.23 ±0.03 vs. 0.19 ±0.05 h−1), or volume of distribution (0.79±0.11 vs. 0.84±0.12 L/kg). The ratio of cortisol area under the concentration versus time curve (AUC) 0–24 hours after prednisone administration to the AUC under baseline conditions was used as a measure of adrenal suppression. This ratio was not significantly different after prednisolone with and without ketoconazole (0.40 ±0.10 vs. 0.45 ±0.03). Renal excretion of prednisone and prednisolone was not significantly changed with ketoconazole. Based on this preliminary study, ketoconazole minimally alters prednisolone clearance in contrast to the significant ketoconazole–methylprednisolone interaction previously reported.

The Pharmacokinetics and Pharmacodynamics of Methylprednisolone in Chronic Renal Failure.

Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion, circulating T-cells, and basophils in blood were compared in six chronic renal failure (CRF) subjects and six healthy controls after an IV administration of MP 0.6 mg kg-1 as the sodium succinate ester. The CRF subjects were studied between hemodialysis treatments. The total clearance of methylprednisolone sodium succinate (the prodrug) was reduced by 40% in CRF; however, the pharmacokinetics of methylprednisolone remained unchanged. Methylprednisolone clearance was approximately 280 ml h-1 kg-1 and volume of distribution was about 1.1 L kg-1. Physiological pharmacodynamic models were applied for the immediate effects of MP, based on the premise that receptor binding is followed by rapid suppression of the secretion of cortisol and recirculation of basophils, T-helper cells, and T-suppressor cells, which persist until inhibitory concentrations (IC50) of methylprednisolone disappear. The difference in (IC50) for each pharmacodynamic parameter was not statistically significant, suggesting no difference in the responsiveness of these factors to methylprednisolone in CRF. As the pharmacokinetics of other corticosteroids are altered in CRF, the lack of pharmacokinetic and pharmacodynamic changes of methylprednisolone may engender a therapeutic advantage for this corticosteroid in CRF.

Pharmacokinetics of Methylprednisolone Hemisuccinate and Methylprednisolone in Chronic Liver Disease

The disposition of methylprednisolone (MP) and its prodrug hemisuccinate (MPHS) was assessed in six middle‐aged patients with chronic liver disease (CLD) and compared with six younger, healthy subjects after a single IV dose of 25.4 mg of MPHS. Blood and urine samples were collected over 12 hours. Plasma and urine concentrations of MPHS and MP and plasma cortisol were measured by HPLC. MPHS clearance (CL) was significantly reduced in the CLD group (495 vs. 1389 mL/hr/kg) whereas volume of distribution (Vss) of MPHS (about 0.35 1/kg) did not differ. The elimination half‐life, t1/2β, was significantly longer in CLD (0.61 vs. 0.32 hr). The percent recovery of unchanged MPHS in urine was similar (about 9%) in both groups. The kinetic parameters of MP did not differ between the two groups for: clearance (about 370 L/hr/kg IBW), Vss (about 1.3 L/kg), and t1/2β (about 3.0 hr). The suppression t1/2 of cortisol after MPHS was longer (3.9 vs. 1.9 hr) indicating metabolic pathways for cortisol and MP are affected differently in CLD. Reduction in MPHS CL may reflect altered hepatic blood flow due to both cirrhosis and age effects. However, good availability of MP from MPHS and lack of perturbation of MP pharmacokinetics in CLD patients may provide therapeutic advantages in selection of this glucocorticoid. This is the first study that characterizes the disposition of the prodrug MPHS and the formation of MP simultaneously in CLD patients.

Population Pharmacokinetic Modeling of Armodafinil and Its Major Metabolites

Population pharmacokinetic models for armodafinil and its major metabolites, R‐modafinil acid and modafinil sulfone, were developed, and selected covariates were investigated. Data from 583 healthy subjects and patients with bipolar I disorder in 11 phase 1–3 studies (8027 concentrations) of armodafinil, given as single or multiple once‐daily doses (50‐ to 400‐mg tablet or capsule), were pooled. A previously developed 1‐compartment model with first‐order absorption without covariate effects was initially applied to pooled phase 1 and 2 data. After covariate analysis, the phase 3 data were pooled with the phase 1 and 2 data set and the model was refined again using a second backward elimination step. Population modeling was performed with NONMEM version 7 with the first‐order conditional estimation method. Estimated armodafinil apparent oral clearance (CL/F), volume of distribution (Vc/F), and absorption t½ were 2.01 L/h, 45 L, and 0.226 hours, respectively. Armodafinil CL/F and Vc/F increased with weight; predicted steady‐state area under the curve was 16.4% higher and 29.1% lower in a patient weighing 50 or 150 kg, respectively, relative to a 70‐kg patient. Female participants had 10.2% lower armodafinil Vc/F compared with male participants. Age, race (white vs nonwhite), health status (healthy vs bipolar I disorder), liver function, and renal function were not statistically significant predictors of armodafinil pharmacokinetics. CL/F and Vc/F for R‐modafinil acid and modafinil sulfone were 16.7 L/h and 8.95 L and 6.82 L/h and 12.4 L, respectively. Weight did not affect exposure of either metabolite. These population pharmacokinetic models were from the largest population of adults reported to date and provide a robust characterization of the pharmacokinetics of armodafinil, R‐modafinil acid, and modafinil sulfone in adults.