William J. Jusko

Comparison of Four Basic Models of Indirect Pharmacodynamic Responses

Four basic models for characterizing indirect pharmacodynamic responses after drug administration have been developed and compared. The models are based on drug effects (inhibition or stimulation) on the factors controlling either the input or the dissipation of drug response. Pharmacokinetic parameters of methylprednisolone were used to generate plasma concentration and response-time profiles using computer simulations. It was found that the responses produced showed a slow onset and a slow return to baseline. The time of maximal response was dependent on the model and dose. In each case, hysteresis plots showed that drug concentrations preceded the response. When the responses were fitted with pharmacodynamic models based on distribution to a hypothetical effect compartment, the resulting parameters were dose-dependent and inferred biological implausibility. Indirect response models must be treated as distinct from conventional pharmacodynamic models which assume direct action of drugs. The assumptions, equations, and data patterns for the four basic indirect response models provide a starting point for evaluation of pharmacologie effects where the site of action precedes or follows the measured response variable.

General pharmacokinetic model for drugs exhibiting target-mediated drug disposition.

Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents. Simulations show that model predicted plasma concentration vs. time profiles are expected to be polyexponential with steeper distribution phases for lower doses and similar terminal disposition phases. Noncompartmental parameters always show apparent Vss and CLD decreasing with dose, but apparent clearance decreases only when the binding process produces drug elimination. The proposed model well captured the time-course of drug concentrations for the aldose reductase inhibitor imirestat, the endothelin receptor antagonist bosentan, and recombinant human interferon-β 1a. This type of model has a mechanistic basis and considerable utility for fully describing the kinetics for various doses of relevant drugs.

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.

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 Llkg). 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 < 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.

Introduction of a Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite

Venlafaxine is a structurally novel, nontricyclic compound that is being evaluated for the treatment of various depressive disorders. A randomized three‐period crossover study was conducted to obtain pharmacokinetic and dose proportionality data on the drug and its active metabolite, O‐desmethylvenlafaxine. Eighteen healthy young men received single doses of venlafaxine 25, 75, and 150 mg followed by 3 days of administration every 8 hours (q8h). Steady‐state elimination half‐life was 3 to 4 hours for venlafaxine and 10 hours for O‐desmethylvenlafaxine; both were independent of dose. Venlafaxine had a high oral‐dose clearance, ranging from 0.58 to 2.63 L/hr/kg across doses with the lowest mean clearance, 0.98 L/hr/kg, at the highest dose. The apparent clearance of O‐desmethylvenlafaxine was lower than venlafaxine, ranging from 0.21 to 0.66 L/hr/kg, and the lowest mean clearance, 0.33 L/hr/kg, occurred at the lowest dose. The area under the metabolite curve was two to three times greater than that for venlafaxine. Each compound had linear dose proportionality up to 75 mg q8h. A composite parameter incorporating venlafaxine plus O‐desmethylvenlafaxine was introduced (i.e., AUC [area under the curve] + activity factor · AUCm), which extended linearity to 150 mg q8h. In summary, venlafaxine is a high‐clearance drug that forms a metabolite with almost equal activity and demonstrates linear dose‐proportionality.

Pharmacokinetics of tacrolimus in liver transplant patients

To characterize the pharmacokinetics of the immunosuppressive agent tacrolimus (FK 506) in liver transplant patients.

Dose dependent pharmacokinetics of prednisone and prednisolone in man

Six healthy male volunteers were given 5, 20, and 50 mg of oral prednisone and 5, 20, and 40 mg doses of intravenous prednisolone. Plasma and urine concentrations of prednisone and prednisolone were determined by HPLC, and the binding of prednisolone to plasma proteins was measured by radioisotopic and equilibrium dialysis techniques. The pharmacokinetics of both oral prednisone and intravenous prednisolone were dose-dependent. The mean oral dose plasma clearances of prednisone ranged from 572 ml/min/ 1.73 m2for the 5mg dose to 2271 ml/min/1.73 m2for the 50 mg dose. Changes in prednisone half-life were insignificant, but increases in the half-life of its metabolite were dose-dependent. The systemic plasma clearance of i.v. prednisolone was dose-dependent and increased from 111 to 194 ml/min/1.73 m2over the 5 to 40 mg i.v. dosage range. The steady-state volume of distribution also increased, but little change in mean transit time and half-life was found. The binding of prednisolone to plasma proteins was markedly concentration-dependent, and a two compartment, nonlinear equation was used to characterize the effective binding of prednisolone to transcortin and albumin. The apparent pharmacokinetic parameters of protein-free and transcortin-free prednisolone were relatively constant with dose. The interconversion of prednisone and prednisolone varied with time and dose, although prednisolone concentrations dominated by 4-to 10-fold over prednisone. In urine, 2–5% of either administered drug was excreted as prednisone and 11–24% as prednisolone. The apparent renal clearances of both steroids were also nonlinear and unrelated to protein binding. These studies indicate that the pharmacokinetics of prednisone and prednisolone are dose-dependent and that protein binding does not fully explain their apparent nonlinear distribution and disposition.

Role of tobacco smoking in pharmacokinetics.

The pervasiveness of tobacco use in our society and the frequency of altered disposition and pharmacological effects of many common therapeutic and recreational drugs in smokers make it apparent that the smoking habit should be considered as one of the primary sources of drug interactions in man. Most of the experimental work in man, animals, and tissue on enzyme systems indicates that the dominant effect of smoking is enhanced disposition caused by induction of hepatic microsomal enzymes. The primary causal agents are probably the polynuclear aromatic hydrocarbons, which are potent and persistent in tissues. While several of the hepatic microsomal drug-metabolizing enzymes are stimulated in smokers, the selectivity of this enhancement in activity is unpredictable and the effects of tobacco smoke on other potential rate-limiting disposition processes are largely unexplored.

Gender‐based effects on methylprednisolone pharmacokinetics and pharmacodynamics

The pharmacokinetics and selected pharmacodynamic responses to methylprednisolone were investigated in six men and six premenopausal women after a dose of 0.6 mg/kg ideal body weight. Women (luteal phase) exhibited a greater methylprednisolone clearance (0.45 versus 0.29 L/hr/kg) and shorter elimination half‐life (1.7 versus 2.6 hours) than men. The volume of distribution of methylprednisolone was similar when normalized for ideal body weight. Pharmacodynamic models were used to examine the methylprednisolone suppressive effects on cortisol secretion and basophil and helper T lymphocyte trafficking. A significantly smaller 50% inhibitory concentration (IC50) value (0.1 versus 1.7 ng/ml) was seen in the women for suppression of cortisol secretion, indicating increased sensitivity. However, the area under the concentration‐time curve of effect was similar for both groups. The IC50 values for effects of methylprednisolone on basophil trafficking related to estradiol concentrations in a log‐linear fashion in women, with increased sensitivity found at higher estradiol concentrations. Men displayed a greater 402‐hour net suppression in blood basophil numbers, but no difference was observed in net cortisol and helper T lymphocyte suppression between the sexes. These findings suggest that methylprednisolone dosages should be based on ideal body weight. Although women are more sensitive to methylprednisolone as measured by cortisol suppression, they eliminate the drug more quickly, generally producing a similar net response.

Gentamicin disposition and tissue accumulation on multiple dosing

Gentamicin pharmacokinetics was examined in a group of 47 patients with stable renal function treated an average of 10 days for severe infection. Serum concentrations rose continually during treatment, and declined in two phases after the drug was stopped, with a mean half-life of 112hr (range 27–693 hr) in the second phase. A two-compartment model was used to describe the biphasic decline in serum concentrations and to calculate the amount of drug in the tissue compartment at all times during and after treatment. Predicted tissue amounts of gentamicin rose continually on multiple dosing in all patients. In six patients who died, postmortem tissues were obtained to quantitate recovery. In all cases, the predicted amount of gentamicin in tissues was in close agreement with the amount recovered at autopsy. Tissue distribution and accumulation constitute a major reason for variability in gentamicin pharmacokinetics and explain both the rising peak and trough serum concentrations and the prolonged detection of gentamicin in serum and urine after the drug is stopped.