Mathematical modeling of the circadian dynamics of the neuroendocrine-immune network in experimentally induced arthritis.

The circadian dynamics of important neuroendocrine-immune mediators have been implicated in progression of rheumatoid arthritis pathophysiology, both clinically as well as in animal models. We present a mathematical model that describes the circadian interactions between mediators of the hypothalamic-pituitary-adrenal (HPA) axis and the proinflammatory cytokines. Model predictions demonstrate that chronically elevated cytokine expression results in the development of adrenal insufficiency and circadian variability in paw edema. Notably, our model also predicts that an increase in mean secretion of corticosterone (CST) after the induction of the disease is accompanied by a decrease in the amplitude of the CST oscillation. Furthermore, alterations in the phase of circadian oscillation of both cytokines and HPA axis mediators are observed. Therefore, by incorporating the circadian interactions between the neuroendocrine-immune mediators, our model is able to simulate important features of rheumatoid arthritis pathophysiology.

Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine, medetomidine, and dexmedetomidine in the horse: a population analysis.

The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2-adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half-maximal effect (IC50 ) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data.

Extracting global system dynamics of corticosteroid genomic effects in rat liver.

One of the challenges in constructing biological models involves resolving meaningful data patterns from which the mathematical models will be generated. For models that describe the change of mRNA in response to drug administration, questions exist whether the correct genes have been selected given the myriad transcriptional effects that may occur. Oftentimes, different algorithms will select or cluster different groups of genes from the same data set. A new approach was developed that focuses on identifying the underlying global dynamics of the system instead of selecting individual genes. The procedure was applied to microarray genomic data obtained from rat liver after a large single dose of methylprednisolone in 52 adrenalectomized rats. Twelve clusters of at least 30 genes each were selected, reflecting the major changes over time. This method along with isolating the underlying dynamics of the system also extracts and clusters the genes that make up this global dynamic for further analysis as to the contributions of specific mechanisms affected by the drug.

Role of dosage regimen in controlling indirect pharmacodynamic responses.

The role of drug delivery in controlling indirect pharmacodynamic responses was assessed via computer simulations and literature review. Simulations of responses related to basic indirect response mechanisms were performed for various drug input rates which allowed the importance of drug delivery rate on the overall pharmacodynamic response to be evaluated. Response versus time profiles of integrated or net responses and efficiency were examined. Rate of drug input has the greatest influence on the area under the effect curve when doses are larger and target drug concentrations are above the IC(50)/SC(50). The pharmacodynamics of drugs which elicit indirect pharmacologic responses such as corticosteroids, diuretics, growth hormone, erythropoietin and insulin indicate that sustained drug delivery enhances the therapeutic efficiency and pharmacodynamic availability.

Partial pharmacodynamic model for the circadian-episodic secretion of cortisol in man.

A pharmacodynamic model was developed to facilitate computer analysis of the circadian-episodic influx of cortisol into plasma from the adrenal gland. The model consists of a catenary system of a biorhythmic control, the adrenal gland, and a body compartment containing circulating cortisol. Computer nonlinear regression analysis was carried out on data consisting of plasma cortisol concentrations measured at 30-min intervals over 1 day in a group of normal children. Circadian rhythmic synthesis of cortisol by the adrenal gland was described by a sinusoidal function which provides the level (284 plus or minus 50 mugg/h/m2) and amplitude (245 plus or minus 50 mug/h/m2) of the synthesis rate and the period (24 hours) and acrophase (8.14 plus or minus 1.95 h) of the cycle. Cosinor analysis of the data confirmed a highly significant circadian rhythm in the daily synthesis rate of cortisol. Episodic secretion, described by an empirical switch function, is assumed to result from accumulation of small amounts of cortisol precursors in the adrenal gland and intermittent stimulation of cortisol release by ACTH. This was found to take place over 46.6 plus or minus 2.4% of a 24-h day. Circulating cortisol is contained in a single body compartment with an apparent volume of distribution (5.3 plus or minus 0.55 liters/m2) from which elimination occurs by first-order metabolic clearance. The biological half-life averaged 0.96 plus or minus 0.18 h. Upon least-square optimization of selected kinetic parameters, the circadian-episodic model increases the accountable variation (r2 x 100) to 89% in comparison with the 35% obtained by use of only a periodic function.

Prednisolone disposition and protein binding in oral contraceptive users.

Combined estrogen-progestogen oral contraceptives (OC) have been shown to alter the metabolism of certain drugs, including corticosteroids, as well as affect circulating protein concentrations. To assess these effects with regard to prednisolone, the pharmacokinetics and protein binding of this steroid were evaluated in eight female OC users and compared with results from eight male and five female non-OC users. All volunteers received 40 mg prednisolone, iv, and steroid concentrations were measured by high pressure liquid chromatography. Plasma clearance of total prednisolone in females on OC was 96 +/- 9 (SD) ml/min X 1.73 m2, significantly (P less than 0.001) lower than those in both male and female controls (205 +/- 46 and 187 +/- 22 ml/min X 1.73 m2). The prednisolone half-life and mean residence time were longer, while the steady state volume of distribution was smaller for OC users. Unbound prednisolone was measured by equilibrium dialysis, and pharmacokinetic and protein binding parameters were calculated from free prednisolone concentrations. A significantly higher (2-fold) concentration of transcortin was found in OC users. Evaluation of free prednisolone parameters showed a significantly lower clearance and decreased volume of distribution, without alteration of the mean residence time for the OC users. Dual OC effects on binding and elimination of prednisolone occur with the net result of a 2-fold increase in the area under the free concentration-time curve, indicative of a marked reduction in the biotransformation rate of the steroid.

Physiologic indirect response models characterize diverse types of pharmacodynamic effects.

A family of four basic physiologic indirect response models has been proposed to account for the pharmacodynamics of drugs that act by way of inhibition or stimulation of the production or loss of endogenous substances or mediators. Such models were applied previously to account for the anticoagulant effects of warfarin, adrenal suppression by corticosteroids, cell trafficking effects of corticosteroids, antipyretic effects of ibuprofen, and aldose reductase inhibition. Additional responses that can be readily characterized with such models include muscular contraction from pyridostigmine, diuresis from furosemide, bronchodilation from terbutaline, prolactin secretion after cimetidine, and potassium suppression by terbutaline. This report shows that indirect response models, rather than "link" or "hypothetical effect compartment" models, may be more appropriate for diverse drugs when time lags exist between plasma or biophase drug concentrations and the time course of pharmacodynamic responses.

Renal clearance and tissue accumulation of gentamicin.

Multiple-dose studies of gentamicin pharmacokinetics were performed in 2 treated patients. After the final dose, serum and urine concentration declined in biphasic fashion with beta half-lives of 87 and 173 hr. Recovery of the total dose administered required urine collection for at least 10 to 20 days after the last dose. A two-compartment model was used to describe the biphasic decline in serum concentrations, to simulate all measured concentrations during treatment, and to predict the amount of gentamicin in the tissue compartment. Analysis of autopsy tissues yielded the predicted amount of drug. A linear two-compartment model adequately quantitates gentamicin disposition until about 4 days after cessation of therapy when gentamicin renal clearance begins to decline because of tubular reabsorption.

Diphenylhydantoin elimination kinetics in overdosed children.

Diphenylhydantoin (DPH) elimination was studied in 4 overdosed children who presented with serum concentrations ranging from 44 to 76 mg/l. Serum was assayed for DPH and urine was assayed for both DPH and 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH). The serum and urine data were subjected to simultaneous computer nonlinear regression analysis using a one-compartment pharmacokinetic model, which accounts for much of the known disposition kinetics of DPH. Computed values for the apparent in vivo Michaelis-Menten constants, K-M and V max, were compared with values derived from data in the literature for normal adult subjects. A trend toward relatively lower K-M and higher V max/K-M values was seen in children. Patients with higher V max values had greater urinary excretion rates of HPPH which, at high serum levels of DPH, were relatively constant except for an apparent diurnal rhythm. The time of onset of DPH toxicity in the children was related to the magnitude by which the rate of DPH administration exceeded the V max values.

Pharmacokinetics of ampicillin in cirrhosis.

Ampicillin pharmacokinetics was studied in 9 cirrhotic patients and in 8 healthy subjects to assess liver disease-related differences in distribution, elimination, and bioavailability of ampicillin. Plasma, urine, and ascites fluid samples were analyzed microbiologically. After intravenous doses, the cirrhotic patients have lower initial plasma concentrations of ampicillin because of the larger volume of distribution. Such patients usually have diminished renal function, which, because renal tubular secretion is the main route of excretion of ampicillin, causes prolonged retention of ampicillin. Metabolic-biliary clearance of ampicillin, normally accounting for removal of only 10% of the dose in normal subjects, is three times as great in cirrhotic patients. Peak ascites fluid concentrations of ampicillin ranged from 2 to 7 mcg/ml after 600 mg iv doses, and very slow clearance of ampicillin from the peritoneal cavity results in persistence in this compartment. Though absorption of ampicillin from capsules was often erratic, its bioavailability was similar in normal and cirrhotic subjects. These findings suggest that the usual course of ampicillin therapy of infections should not be altered in cirrhotic patients. On the other hand, reduction in dosage may be called for when there is renal impairment.

Bioavailability of hydrocortisone retention enemas in relation to absorption kinetics.

The rate and extent of absorption of hydrocortisone from two commercial formulations of rectal enemas were determined in 12 normal subjects. The bioavailability of the enema was related to its absorption rate constant. Four subjects absorbed hydrocortisone slowly from both enemas at a mean rate of 0.361 hr-1 and five subjects absorbed hydrocortisone rapidly from both preparations at a mean rate of 1.05 hr-1 (p < 0.001). The bioavailability of hydrocortisone retention enemas ws 0.810 and 0.502 in slow and rapid absorbers (p < 0.01).

Determination of procainamide acetylator status.

Variation in renal function can obscure the measurement of acetylator status for compounds such as procainamide in which appreciable active drug or acetyl metabolite is excreted in urine. Computer simulations and patient studies were used to compare two common metabolite/drug ratio methods and a proposed clearance technique for phenotyping acetylation rate. The calculation of apparent acetylation clearance from steady-state serum concentrations of procainamide and urinary excretion rates of N-acetyl-procainamide provides the most definitive discrimination between fast and slow acetylators.

Tissue and erythrocyte distribution of digoxin in infants.

The distribution of digoxin in the myocardium, skeletal muscle, erythrocytes, and plasma (or serum) was studied in 19 infants. There was a linear relationship between myocardium and serum concentrations and no saturation was observed over the serum concentration range of 0.5-8.6 ng/ml. Myocardium uptake of digoxin was nearly twice as great in infants as in adults at any given serum concentration. Erythrocyte: plasma concentration ratios of digoxin were one-third smaller during digitalization than during maintenance digoxin therapy. The latter ratios were also three times greater in infants than found previously in adults. Their findings are consistent with a greater apparent volume of distribution of digoxin in infants and may partly explain the unusually large therapeutic doses needed in infants.

Ketoconazole effects on methylprednisolone disposition and their joint suppression of endogenous cortisol.

The effects of ketoconazole and methylprednisolone on endogenous cortisol were studied in eight normal subjects. Intravenous methylprednisolone sodium succinate was given alone in doses of 15 or 30 mg. The methylprednisolone dose was reduced by 57% when ketoconazole was administered chronically for 1 week to seek equivalent methylprednisolone AUCs by compensating for the expected reduction in methylprednisolone clearance. Ketoconazole decreased clearance by 46% and increased mean residence time by 37%. The ratio of the cortisol AUC during each drug treatment compared with baseline conditions was used to assess the net extent and duration of cortisol suppression. This cortisol AUC ratio was reduced from 0.45 (methylprednisolone) to 0.39 (methylprednisolone plus ketoconazole), suggesting that ketoconazole modestly enhanced (P less than 0.01) cortisol suppression. Based on the reduction in methylprednisolone clearance and cortisol AUC by ketoconazole, a 50% lower dose of methylprednisolone during concomitant therapy with ketoconazole is recommended.

Lack of pharmacokinetic and pharmacodynamic interactions between ketoconazole and prednisolone.

The effects of ketoconazole on the pharmacokinetics and pharmacodynamics of intravenous prednisolone (14.8 mg) were assessed in six healthy volunteers. Subjects were studied with and without receiving ketoconazole, 200 mg orally for 6 days. The addition of ketoconazole did not significantly change the clearance (96 +/- 11 versus 90 +/- 11 ml/hr/kg), mean residence time (4.29 +/- 0.43 versus 4.45 +/- 0.59 hours), volume of distribution (0.41 +/- 0.02 versus 0.40 +/- 0.02 L/kg), or plasma protein binding characteristics of prednisolone. The suppressive effects of prednisolone on serum cortisol, blood basophil, and helper T lymphocyte values, assessed by the ratio of the area under the curve (AUC) after prednisolone administration to the baseline AUC, was not altered significantly by ketoconazole. The 50% inhibitory concentration values derived from pharmacodynamic models developed to describe the direct suppressive effects of corticosteroids indicated no alteration in intrinsic sensitivity in the presence of ketoconazole. Ketoconazole does not appear to alter the pharmacokinetics or the pharmacodynamic response patterns of selected direct suppression effects of single low doses of prednisolone.

Pharmacoimmunodynamic interactions of interleukin-10 and prednisone in healthy volunteers.

OBJECTIVE: The pharmacoimmunodynamic interactions of recombinant human interleukin-10 and prednisolone were examined in 12 normal male volunteers. METHODS: Single doses of interleukin-10 (8 microg/kg subcutaneous injection), interleukin-10 with prednisone (15 mg by mouth), placebo with prednisone, or placebo were administered. Drug concentrations yielded pharmacokinetic parameters. Response measurements included whole blood lipopolysaccharide-stimulated cytokine (tumor necrosis factor-alpha, interleukin-1beta) production, phytohemagglutinin-stimulated whole blood lymphocyte proliferation, and differential white blood cell counts (including monocytes, lymphocytes, and neutrophils). Extended indirect-response models were used to deal with diverse drug interactions in assessing single and joint effects of interleukin-10 and prednisolone. RESULTS: No pharmacokinetic alterations in interleukin-10 or prednisolone were found. Dosing with interleukin-10 produced strong inhibition of ex vivo cytokine production for the 24-hour postdosing period, whereas prednisolone, the active form of prednisone, was partly inhibitory for only 3 hours. Prednisolone significantly inhibited (P < .05) ex vivo lymphocyte proliferation for 6 hours, whereas interleukin-10 failed to alter this measure. Their joint effects on these responses were inhibitory consonant with the stronger agent. Marked changes in various leukocyte kinetics occurred. The steroid caused monocytopenia, lymphocytopenia, and neutrophilia, with IC50 or SC50 values of 10 to 20 ng/mL. Interleukin-10 elevated monocytes and neutrophils and lowered lymphocyte counts, with IC50 or SC50 values of 0.7 to 1.3 ng/mL. Dynamic modeling showed loss of prednisolone effects on monocytes and additive steroid/interleukin-10 effects on lymphocytes and neutrophils, with neutrophils exhibiting greater changes in net response. CONCLUSION: Interleukin-10 and prednisolone interacted favorably for the measured pharmacoimmunodynamic indices with no kinetic alterations but net responses that were similar to or greater than effects produced by the more strongly acting agent.

Effect of smoking on theophylline disposition.

The pharmacokinetics of theophylline were examined in a group of nonsmokers and in heavy smokers (1 to 2 packs/day) before and 3 to 4 mo after cessation of cigarette smoking. The half-life of theophylline in smokers averaged 4.3 (SD = 1.4) hr, significantly shorter than the mean value in nonsmokers (7.0, SD =1.7 hr). The apparent volume of distribution of theophylline was somewhat larger in smokers (0.50 +/-0.12 L/kg) than in nonsmokers (0.38 +/-0.04 L/kg). The body clearance of theophylline was appreciably larger and relatively more variable in smokers (100 +/-44 ml/min/1.73 m2) than in nonsmokers (45 +/-13 ml/min/1.73 m2). Serum concentrations of thiocyanate, a biotransformation product of cyanide which is inhaled with smoke, were used to monitor the smoking status of the subjects. The body clearances of theophylline showed a good correlation (r = 0.785, p less than 0.001) with the serum thiocyanate concentrations. Of the 8 smokers, only 4 managed to refrain from smoking for at least 3 mo, and these subjects showed no significant change in theophylline elimination. The increase in theophylline clearance caused by smoking is probably the result of induction of drug-metabolizing enzymes that do not readily normalize after cessation of smoking.

Theophylline disposition in obesity.

Theophylline disposition was examined in 14 obese subjects and 57 normal subjects. A single oral dose of aminophylline solution was given and serum and saliva samples were collected over several hours and assayed by high-pressure liquid chromatography. The apparent volume of distribution (Vd) and body clearance (ClB) were analyzed for total body weight (TBW) and ideal body weight (IBW). The Vd averaged 0.482 (SD = 0.084) L/kg TBW in normals vs 0.382 (0.069) L/kg TBW and 0.77 (0.189) L/kg IBW in obese subjects. The ClB averaged 63.0 (28.5) ml/hr/kg IBW in normals compared to 32.8 (11.1) ml/hr/kg TBW and 64.1 (20.8) ml/hr/kg IBW in obese subjects. Similar Vd values between the two groups when TBW is used indicates that loading dose is best calculated based on TBW. Similar ClB based on IBW in normal and obese subjects indicates that IBW should be used to calculate maintenance doses for theophylline. Mean half-lives were longer in obese subjects than in normals, 8.6 (2.0) and 6.0 (2.1) hr, respectively, suggesting that obese patients may need less frequent dosing.

Prednisolone disposition in obese men.

Obesity is accompanied by altered secretion and disposition of sex and glucocorticoid hormones, including cortisol, and also confounds parameter normalization and drug dosage selection relative to body weight. Prednisolone disposition was assessed in eight obese and four normal male subjects after a dose of 33 mg iv. Steroid concentrations were determined by HPLC. Kinetics were related to ideal body weight (IBW) and total body weight (TBW). Uncorrected steady-state volume of distribution (Vss) of total prednisolone was 20% greater in obese subjects (36.7 and 44.1 l). This effect could be described by the relationship: Vss = 0.54 IBW + 0.09(TBW-IBW), with a distribution coefficient of 0.09 reflecting limited prednisolone uptake by fat. Protein binding parameters and albumin and transcortin concentrations were similar between groups. Uncorrected total and free prednisolone clearances (Cl) were increased in obesity (11.1 and 8.3 l/hr total; 65.4 and 46.5 l/hr free). Free prednisolone Cl correlated strongly (r = 0.80) with degree of obesity expressed as TBW/IBW. In the obese, endogenous cortisol concentrations were initially higher before exogenous steroid dosing, were suppressed at an identical rate, and returned to baseline more slowly than in normal subjects. The apparent hypersensitivity of the adrenal gland offsets the increased Cl of free prednisolone in obesity, indicating that weight-proportional dosage adjustments of this steroid in obesity should reflect TBW.

Pharmacokinetics of single and multiple doses of ethinyl estradiol and levonorgestrel in relation to smoking.

The effects of tobacco and oral contraceptive (OC) use (Ovral) on the pharmacokinetics of levonorgestrel (0.25 mg) and ethinyl estradiol (50 micrograms) were examined. Young women (n = 27) were grouped as follows: I: non-OC users/nonsmokers; II: OC users/nonsmokers; III: non-OC users/smokers; and IV: OC users/smokers. The apparent clearance of levonorgestrel in group I was 80.9 +/- 15.6 ml/hr/kg and the half-life was 19.3 hours. A significant decrease in levonorgestrel clearance was seen in the chronic OC users (groups II and IV). The apparent oral clearance of ethinyl estradiol was 1002 +/- 398 ml/hr/kg in group I and the half-life averaged 7.7 hours. Groups II and III showed decreased (not significant) clearance of ethinyl estradiol. Tobacco use had no effect on steroid pharmacokinetics in the non-OC users. Although chronic OC use did not affect ethinyl estradiol clearance, a joint effect of tobacco/OC use on enhancing clearance of ethinyl estradiol appeared to occur. A linear relationship was found between 24-hour trough serum concentrations and AUC values of both steroids that may facilitate population monitoring studies of OC exposure.

PIP: The effects of combined cigarette smoking and oral contraceptive (OC) use on the pharmacokinetics of the pill's major components were examined in 27 white female volunteers grouped as follows: Group 1, non-OC user, nonsmoker; Group 2, OC user, nonsmoker; Group 3, non-OC user, smoker; Group 4, OC user, smoker. The 11 OC users in the study had been taking the pill for over 6 months; 5 were taking Ovral (50 mcg of ethinyl estradiol, 0.5 mg of norgestrel) and the remaining 6 switched to Ovral for the 1-month cycle before the study period. The non-OC users took 1 study dose of Ovral. The clearance of levonorgestrel was significantly lower in chronic OC users (mean elimination half-life of 30 hours) than in single-dose subjects (mean elimination half-life of 23 hours). The mean elimination half-life of ethinyl estradiol was approximately 12 hours for both chronic and acute OC use, although there was a nonsignificant tendency for lower ethinyl estradiol clearances in chronic OC users. Chronic tobacco use as a single factor did not influence the pharmacokinetics of levonorgestrel; however, a joint effect from chronic OC use and tobacco use was seen for ethinyl estradiol. Tobacco use had no effect on steroid pharmacokinetics in the non-OC users. Finally, a linear relationship was found between 24-hour trough serum concentrations and area-under-curve values of both steroids that may facilitate population monitoring studies of OC exposure.