Biomedical subjects

W J Jusko

Publications and source records attributed to W J Jusko.

At least 37 records · Page 2Linked to original sources

PubMed1999

Role of baseline parameters in determining indirect pharmacodynamic responses.

Indirect Response Models account for the pharmacodynamics of numerous drugs which inhibit or stimulate the production (k(in)) or loss (k(out)) of the response variable (R). The dose and pharmacokinetics, capacity (S(max), I(max)), and potency (SC(50), IC(50)) factors of the Hill function incorporated in these models are the primary determinants of overall responsiveness. However, the initial or baseline value for the response (R(0) = k(in)/k(out)) should also be considered as an important factor for the net response. Using Indirect Response Model III (stimulation of input) as an example, the net area under the effect curve (AUEC(NET)) can be proportional to the R(0) values. Such a feature is demonstrated in this report by computer simulations, by examination of the integral of the simulated response vs time profiles, and with examples from the literature. Also shown is an adjustment of R(0) when the therapeutic agent is an endogenous substance. These analyses show that the role of R(0) and k(in) should not be overlooked as determinants of indirect responses and source of variation among subjects or patient groups.

Algorithms↗

PubMed1999

Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers.

PURPOSE: To examine the pharmacokinetics (PK) and pharmacodynamics (PD) of ipamorelin, a growth hormone (GH) releasing peptide, in healthy volunteers. METHODS: A trial was conducted with a dose escalation design comprising 5 different infusion rates (4.21, 14.02, 42.13, 84.27 and 140.45 nmol/kg over 15 minutes) with eight healthy male subjects at each dose level. Concentrations of ipamorelin and growth hormone were measured. RESULTS: The PK parameters showed dose-proportionality, with a short terminal half-life of 2 hours, a clearance of 0.078 L/h/kg and a volume of distribution at steady-state of 0.22 L/kg. The time course of GH stimulation by ipamorelin showed a single episode of GH release with a peak at 0.67 hours and an exponential decline to negligible GH concentration at all doses. The ipamorelin-GH concentration relationship was characterized using an indirect response model and population fitting. The model employed a zero-order GH release rate over a finite duration of time to describe the episodic release of GH. Ipamorelin induces the release of GH at all dose levels with the concentration (SC50) required for half-maximal GH stimulation of 214 nmol/L and a maximal GH production rate of 694 mIU/L/h. The inter-individual variability of the PD parameters was larger than that of the PK parameters. CONCLUSIONS: The proposed PK/PD model provides a useful characterization of ipamorelin disposition and GH responses across a range of doses.

Adult↗

PubMed1999

Pharmacokinetic and pharmacoimmunodynamic interactions between prednisolone and sirolimus in adrenalectomized rats.

Prednisolone (Pred) and sirolimus (SIR) are immunosuppressive compounds acting through different mechanisms with moderate synergism found in vitro. Both drugs are metabolized partly by CYP3A enzymes. After i.v. administration of placebo, Pred (5 mg/kg), SIR (1 mg/kg), or Pred with SIR (5 and 1 mg/kg doses) to adrenalectomized male rats, Pred plasma and SIR whole blood concentrations were followed for 48 hr along with circulating T-helper and T-cytotoxic cell counts. Ex vivo whole blood lymphocyte proliferation marked host responsiveness. An extended indirect PK/PD model was used to describe responses to these drugs, alone or combined. An interactive two-stage population analysis showed no modification in drug PK. Mean Pred plasma clearance was 0.655 L/hr (interrat++ variability: 11%) and significantly increased with weight. Mean SIR whole blood volume of distribution and clearance were 5.6 L (62%) and 0.28 L/hr (32%), and animal scaling showed weight-power proportionality. In vitro metabolism studies showed no significant inhibition of Pred or prednisone CYP3A metabolism by SIR (50 microM), but this pathway accounted for less than 5% of Pred metabolism. Pred decreased numbers of T-helper lymphocytes with a mean IC50 of 37.8 nM (21%) alone or 12.3 nM (130%) with SIR. Results for T-cytotoxic lymphocytes were similar. SIR increased lymphocyte numbers with a mean IC50 of 52.2 nM (24%) for T-helper and 28.8 nM (51%) for T-cytotoxic cells. Taking into account drug effects on lymphocyte trafficking, Pred directly inhibited ex vivo lymphocyte proliferation with a mean IC50 of 1.08 nM (38%). SIR, after a transduction step, inhibited proliferation with a mean IC50 of 1.00 nM (26%). Responses measured after drug coadministration were reasonably quantitated by addition of single drug effects. Since, at pharmacologic concentrations in rats, Pred and SIR did not interact in their PK but synergistically or additively interact in their dynamics, their joint therapeutic use is promising. The adrenalectomized rat may be a suitable animal model to characterize drug effects on lymphocyte trafficking and reactivity.

Adrenal Glands↗

PubMed1999

Mathematical modeling of circadian cortisol concentrations using indirect response models: comparison of several methods.

Six mathematical functions to describe the chronobiology of cortisol concentrations were assessed. Mean data from a dose-proportionality study of inhaled fluticasone propionate were fitted with an indirect response model using various biorhythmic functions (single cosine, dual ramps, dual zero-order, dual cosines, and Fourier series with 2 and n-harmonics) for production rate. Data with known parameters and random variation were also generated and fitted using the ADAPT II program. Fitted parameters, model estimation criteria, and runs tests were compared. Models with preassigned functions: the dual ramps, the dual zero-order and the dual cosines provide maximum and minimum times for cortisol release rate, were suitable for describing asymmetric circadian patterns and yielding IC50 values. Fourier analysis differs from the other methods in that it uses the placebo data to recover equations for cortisol secretion rate rather than by postulation. Nonlinear regression for Fourier analysis, instead of the L2-norm method, was useful to characterize the baseline cortisol data but was restricted to a maximum of two harmonics. Apart from the single cosine function, which predicts symmetrical cortisol concentrations, all methods were satisfactory in describing the baseline and suppressed cortisol concentrations. On the other hand, Fourier series with L2-norm produced the best unbiased estimate for baseline patterns. The Fourier method is flexible, accurate, and can be extended to other drug-induced changes in normal periodic rhythms.

Androstadienes↗

PubMed1999

Modeling interactions between adrenal suppression and T-helper lymphocyte trafficking during multiple dosing of methylprednisolone.

A physiologic pharmacodynamic model was developed to jointly characterize the effects of corticosteroid treatment on adrenal suppression and T-helper cell trafficking during single and multiple dosing in asthmatic patients. Methylprednisolone (MP), cortisol, and T-helper cell concentrations obtained from a previously published study during single day and 6 days of multiple dosing MP treatment were examined. The formation and disposition kinetics of MP were described with a compartmental model. The biorhythmic profile of basal cortisol secretion rate was analyzed using a recent Fourier approach based on circadian harmonics. A three-compartment loop model was proposed to represent three major T-helper cell pools: blood, extravascular site, and lymph nodes. T-helper cell synthesis and degradation rate constants were obtained from the literature. The suppressive effects of cortisol and MP on T-helper cell concentrations were described with a joint additive inhibition function altering the cell migration rate from lymph nodes to blood. The model adequately described both plasma cortisol profiles and T-helper cells in blood after single and multiple doses of MP. The potency of MP for suppression of cortisol secretion was estimated as IC50 = 0.8 ng/ml. The biorhythmic nature of the basal T-helper cells in blood was well described as under the influence of basal circadian cortisol concentrations with IC50 = 79 ng/ml. The model fitted potency of MP for suppression of T-helper cells was IC50 = 4.6 ng/ml. The observed rebound of T-helper cells in blood can also be described by the proposed model. The rhythm and suppression of plasma cortisol and T-helper cells before and during single and multiple dose MP treatment were adequately described by these extended indirect response models.

Adrenal Glands↗

PubMed1999

Basic pharmacodynamic models for agents that alter production of natural cells.

Basic indirect pharmacodynamic models for agents which alter the generation of natural cells based on a life-span concept are introduced. It is assumed that cells (R) are produced at a constant rate (kin), survive for a specific duration TR, and then are lost. The rate of cell loss must equal the production rate but is delayed by TR. A therapeutic agent can stimulate or inhibit the production rate according to the Hill function: 1 +/- H(C(t)) where H(C(t)) contains capacity (Smax) and sensitivity (SC50) constants and C(t) is a pharmacokinetic function. Thus an operative model is [equation: see text] with the baseline condition R0 = kin.TR. One- and two-compartment catenary cell models were examined by simulation to describe the role of pharmacokinetics and cell properties. The area under the effect curve (AUCE) was derived. The models were applied to literature data to describe the stimulatory effects of single doses of hematopoietic growth factors such as granulocyte colony-stimulating factor (G-CSF) on neutrophils, thrombopoietin (TPO) on platelets, and erythropoietin (EPO) on reticulocytes in blood. The models described experimental data adequately and provided cell life-spans and SC50 values. The proposed cell production/loss models can be readily used to analyze the pharmacodynamics of agents which alter cell production yielding realistic physiological parameters.

Algorithms↗

PubMed1999

Diltiazem retards the metabolism of oral prednisone with effects on T-cell markers.

The area under the time-plasma concentration curve (AUC) was measured for prednisolone (the major active metabolite of prednisone) after ingestion of 15 mg of prednisone (phase 1) and again after 3 d of oral diltiazem (180 mg/d) followed by the same dose of oral prednisone (phase 2) in eight normal adult patients. Diltiazem increased the prednisolone AUC by 21% (range 3-38%), from 1297 +/- 157 ng/h/mL to 1560 +/- 169 ng/h/mL (p = 0.001). This effect was associated with a greater decrease from baseline in CD3+ lymphocyte number at 4 h after prednisone ingestion (596 +/- 175 vs. 516 +/- 140, p = 0.05), a larger percentage decrease of circulating CD3+ lymphocytes at 8 h (43 +/- 19% vs. 53 +/- 19%, p = 0.04), and a decrease in the number of CD3+ CD8+ T cells at 4 h post-prednisone ingestion (279 +/- 81 vs. 236 +/- 51, p = 0.04). Diltiazem retards prednisolone metabolism and when used chronically with prednisone could conceivably, in some patients, enhance its immunologic and other clinical effects. Potentiation of prednisone side-effects by diltiazem may be of special interest in pediatric patients, and possible diltiazem-prednisone interactions merit study in this population.

Administration, Oral↗

PubMed1999

Pharmacokinetic and adrenal interactions of IL-10 and prednisone in healthy volunteers.

The pharmacokinetic and adrenal interactions of recombinant human interleukin-10 and prednisolone were examined in this open-label, randomized, four-way crossover study in 12 healthy adult male volunteers. Single doses of IL-10 (8 micrograms/kg s.c.), IL-10 with prednisone (15 mg p.o.), placebo with prednisone, or placebo were administered on four separate occasions with at least 3-week interceding washout periods. Measurements included plasma prednisone, prednisolone and cortisol, unbound prednisolone, and serum IL-10 concentrations. Pharmacokinetic parameters were determined using noncompartmental and model-fitting analysis, while area analysis and an indirect response model were used to assess cortisol dynamics. IL-10 exhibited prolonged serum concentrations owing to dual-absorption processes that were largely unaffected by prednisone. The Cmax values were about 3 ng/mL, while the tmax occurred at 7 to 9 hours. Prednisolone exhibited rapid systemic kinetics with a Cmax of 235 ng/mL, tmax at 1.11 hours, and t1/2 of 2.54 hours with no significant alterations owing to IL-10. Both prednisolone and prednisolone/IL-10 caused marked suppression of cortisol concentrations with similar magnitude and IC50 values; however, IL-10 alone significantly increased the 24-hour AUC of cortisol by 20%. Thus, IL-10 and prednisolone do not interact in disposition or adrenal suppression to a clinically significant degree.

Adrenal Glands↗

PubMed1999

Pharmacokinetics and pharmacodynamics of avitriptan during intravenous administration in healthy subjects.

Avitriptan, a selective 5-HT1-like receptor agonist, is an effective compound for the treatment of migraine headaches with a prolonged duration of response. A double-blind, placebo-controlled, parallel-group, ascending-dose study in 24 healthy subjects was designed to assess the safety, tolerance, pharmacokinetics, and pharmacodynamics of avitriptan. This antimigraine drug was administered as two consecutive constant-rate IV infusions at three dose levels (12.7, 25.3, and 38.0 mg), which were targeted to produce plasma concentrations in and above the therapeutic range. The best fitting of the plasma concentration-time data was obtained by using a triexponential function yielding a terminal t1/2 of 8 hours. The areas under the plasma concentration versus time curves were proportional to dose, indicating linear pharmacokinetics. Moreover, the clearance and steady-state volume of distribution values were independent of the dose. The change in pulse rate and supine systolic and diastolic blood pressure was determined as pharmacodynamic effects of avitriptan. A "threshold log-linear" model, which accounts for the linear increase in pharmacodynamic effect with the log of plasma concentrations when the latter was higher than a certain threshold value, adequately described the pharmacodynamic data. The threshold plasma drug concentrations for the pulse rate and the diastolic and systolic blood pressure were 14, 74, and 161 ng/ml, respectively. Overall, avitriptan has consistent, linear pharmacokinetics and increases systolic and diastolic blood pressure in a predictable manner at a higher plasma concentration. However, this drug does not produce a significant change in pulse rate at the dose levels (12.7-38 mg) evaluated in this study.

Adult↗

PubMed1999

Pharmacokinetic and pharmacodynamic interactions between dehydroepiandrosterone and prednisolone in the rat.

The effects of multiple-dosing with dehydroepiandrosterone sulfate (DHEA-SO4) on the pharmacokinetics and pharmacodynamics of prednisolone were examined. Prednisolone (25 mg/kg i.v.) was administered to male and female Sprague-Dawley rats (250-350 g) alone and following DHEA-SO4 (4 mg/kg i.v., every 8 h for 4 days). Male control rats cleared prednisolone faster [3.68 +/- 1.30 (males) vs 1.01 +/- 0.7 l/h/kg; p < 0.05] and had larger Vss (1.38 +/- 0.459 vs 0.394 +/- 0.500 l/kg; p < 0.05) than females both due largely to lesser plasma protein binding. Prednisolone clearance and Vss were not altered by DHEA-SO4 in males or females. The net effect of prednisolone on basophils and plasma corticosterone did not differ with gender. DHEA-SO4 had no effect on plasma corticosterone and did not alter prednisolone action. DHEA-SO4 inhibited basophil trafficking in males, but to a lesser extent than prednisolone, and antagonized the effect of prednisolone on basophil trafficking in both sexes. The steroid-sparing effect observed with DHEA clinically may not be due to an alteration of corticosteroid pharmacokinetics but partly to its ability to affect immune functions.

Adjuvants, Immunologic↗

PubMed1999

A pharmacokinetic/pharmacodynamic model for recombinant human growth hormone effects on induction of insulin-like growth factor I in monkeys.

The pharmacokinetics of recombinant human growth hormone (rhGH) and its effects on the induction of insulin-like growth factor I (IGF-I) were studied in juvenile rhesus monkeys. Disposition profiles of rhGH from two short-term i.v. infusion studies were described by a two-compartment model yielding a clearance of 16.1 ml/min and T1/2 of 2.0 h. Four rhGH treatment groups were included in this study: group A, ProLease rhGH (24 mg), a sustained-release microsphere formulation; group B, a single s.c. injection plus an implanted osmotic pump (24.4 mg); group C, a single s.c. injection (25.9 mg); group D, daily 0.86-mg s.c. injection for 28 days. Their rhGH input profiles were analyzed by a numerical deconvolution method. ProLease and osmotic pump provided zero-order inputs of rhGH and maintained the serum rhGH concentrations around 9 to 13 ng/ml for 16 (group A) and 30 days (group B). For s.c. injections, rhGH underwent first-order absorption. An indirect response model was applied based on use of a Hill function for stimulation of IGF-I production. Parameter values obtained included Smax = 2.2, SC50 = 6.5 ng/ml, and gamma (slope coefficient) = 6.8, which were applicable to all treatments. The area under effect curve showed group B to be most effective for IGF-I induction, whereas group A produced the highest peak level in 16 days. Group C had the lowest induction among the four groups, despite being given the highest dose. Group D had modest IGF-I induction, but the pulsatile rhGH input is less effective than continuous input provided by ProLease. Our pharmacokinetic/pharmacodynamic model demonstrates that ProLease and osmotic pump delivery were best able to maintain rhGH level above the s.c.50 value, which provided more effective IGF-I induction compared with the single or daily subcutaneous injections in solution.

Animals↗

PubMed1999

Pharmacokinetic/Pharmacodynamic models for corticosteroid receptor down-regulation and glutamine synthetase induction in rat skeletal muscle by a Receptor/Gene-mediated mechanism.

Muscle wasting and excessive fat deposition are side effects attendant to chronic corticosteroid treatment. Corticosteroid immunosuppression is necessary in circumstances such as transplantation. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was used to help elucidate the relationships between the events in the molecular cascade that result in muscle wasting and fat deposition by corticosteroids. Specifically, the relationships for receptor/gene-mediated effects that result in increased glutamine synthetase (GS) activity in skeletal muscle were quantitatively analyzed after an i.v. bolus dose of 50 mg/kg methylprednisolone in male adrenalectomized Wistar rats. Profiles of methylprednisolone pharmacokinetics, glucocorticoid receptor density, and its mRNA, GS mRNA, and GS activity in gastrocnemius muscles were determined. The results were used to develop PK/PD models using differential equations in the ADAPT II program. Two indirect response models were tested for the dynamics of glucocorticoid receptor mRNA regulation by activated steroid/receptor complex. Both reduction in message synthesis and message destabilization may be involved but with some tissue specificity. The recovery of active receptor after down-regulation is biphasic. The initial recovery may involve receptor recycling from the nucleus, whereas the later phase may involve de novo synthesis of new receptor protein. The nuclear events and GS mRNA/GS induction in rat skeletal muscle show sequential relationships for each component for corticosteroid actions. The PK/PD models provide mechanism-based methods of quantifying complex processes in receptor/gene-mediated enzyme induction featuring the characteristics of time delay and possible nonlinearity in intact tissues.

Animals↗

PubMed1998

Gender-related assessment of cyclosporine/prednisolone/sirolimus interactions in three human lymphocyte proliferation assays.

BACKGROUND: Cyclosporine (CsA), prednisolone (Pred), and sirolimus (Sir) are immunosuppressive compounds inhibiting lymphocyte proliferation at the cytokine gene transcription (CsA and Pred) or signal transduction (Sir) levels. METHODS: Double- and triple-drug interactions were simultaneously studied using lectin-induced proliferation of isolated cell lymphocytes (ICLP) and whole blood lymphocytes from men and women as well as two-way mixed lymphocyte reaction assays. Drug interactions were described with isobolograms and quantitated with the universal response surface approach by estimating the interaction parameter alpha. RESULTS: All compounds inhibited more than 89% of control proliferative responses. In each assay, CsA was less potent than Pred (3- to 14-fold) and Sir (5- to 11-fold). Sir was of similar or higher potency than Pred and 1.5-fold more potent in men than women. Pred was 1.4 times more potent in women but this was found only in the ICLP assay. All combinations were synergistic (alpha>0), with greater synergism found for combinations involving Sir, especially in the ICLP (alpha>13) and two-way mixed lymphocyte reaction (alpha>40) assays. Moreover, the Sir/Pred interaction in the ICLP assay was two to five times more synergistic in women, because their mean alpha was 56 compared with 13 in men. Double-combination alpha values were able to reasonably describe CsA/Pred/Sir triple-interaction effects. CONCLUSIONS: These studies indicate that CsA, Pred, and Sir act and synergistically interact in vitro, with gender and assay as additional factors, and that whole blood lymphocyte proliferation cultures are useful in assessing the nature and intensity of drug interactions.

Adult↗

PubMed1998

Population pharmacokinetics of sirolimus.

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Clinical Trials as Topic↗

PubMed1998

Integrated functions for four basic models of indirect pharmacodynamic response.

The integrated solutions (ABEC, area between baseline and effect curve) of four basic models of indirect pharmacodynamic responses are developed. These models assume that drug can inhibit or stimulate the production or loss of the response variable. For two models (I and III) with monoexponential drug disposition, explicit formulas for the ABEC were obtained, where ABEC is a function of ln (1 + (D/V)/IC50) or ln (1 + (D/V)/SC50) where D = dose, V = volume, and IC50 or SC50 = 50% effective concentration. Two other models (II and IV) were treated asymptotically with respect to small and large doses. Approximate formulas [e.g., ABEC = constant(1) x ln (1 + (D/V)/IC50) + constant (2)] were derived and the asymptotic behavior of the ABEC was established. In addition, simulations were performed to assess the effects of drug absorption rates and polyexponential disposition on ABEC values. These models show how pharmacokinetic and pharmacodynamic factors jointly determine the net response to a single dose of drug.

Dose-Response Relationship, Drug↗

PubMed1998

Transit compartments versus gamma distribution function to model signal transduction processes in pharmacodynamics.

Delayed effects for pharmacodynamic responses can be observed for many signal transduction processes. Three approaches are summarized in this report to describe such effects caused by cascading steps: stochastic process model, gamma distribution function, and transit compartment model. The gamma distribution function, a probability density function of the waiting time for the final step in a stochastic process model, is a function of time with two variables: number of compartments N, and the expected number of compartments occurring per unit time k. The parameter k is equal to 1/tau, where tau is the mean transit time in the stochastic process model. Effects of N and k on the gamma distribution function were examined. The transit compartment model can link the pharmacokinetic profile of the tested compound, receptor occupancy, and cascade steps for the signal transduction process. Time delays are described by numbers of steps, the mean transit time tau, and the amplification or suppression of the process as characterized by a power coefficient gamma. The effects of N, tau, and gamma on signal transduction profiles are shown. The gamma distribution function can be utilized to estimate N and k values when the final response profile is available, but it is less flexible than transit compartments when dose-response relationships, receptor dynamics, and efficiency of the transduction process are of concern. The transit compartment model is useful in pharmacokinetic/pharmacodynamic modeling to describe precursor/product relationships in signal transduction process.

Animals↗

PubMed1998

Precursor-dependent indirect pharmacodynamic response model for tolerance and rebound phenomena.

A precursor-dependent model of indirect pharmacodynamic response which can describe tolerance and rebound was characterized in terms of the effects of changes in the fundamental properties of the drug on its response profiles. The model extends previous models by considering inhibition or stimulation of production of the response variable dependent on the amount of precursor which may accumulate or deplete after administration of some drugs. Standardized pharmacokinetic and pharmacodynamic parameters were used for generating dose, plasma concentration, and response-time profiles using computer simulations. The peak response (Rmax) and the time of its occurrence (TRmax) were dependent on the dose, degree of maximum inhibition (Imax) or stimulation (Smax), and drug concentrations causing 50% inhibition (IC50) or stimulation (SC50). The maximum rebound (RBmax) and the time of its occurrence (TRBmax) after a single bolus dose were also dependent on these factors, but were of lesser magnitude and showed relatively later occurrence. Interestingly, values of area between the baseline and effect curve (ABEC) and area between the baseline and rebound curve (ABRC) were equal for each set of conditions for each model, but the latter is reduced when there is a second pathway for loss of precursor. Tolerance occurs because of diverse mechanisms, and the response patterns demonstrated may be helpful in describing tolerance and rebound phenomena for drugs which affect precursor pools.

Dose-Response Relationship, Drug↗

PubMed1998

Pharmacokinetics and leukocyte responses of recombinant human interleukin-10.

PURPOSE: To study the pharmacokinetics and ex vivo leukocyte responses of recombinant human IL-10 (rHuIL-10) following single s.c. and i.v. dosing. METHODS: A randomized two-way cross-over study was undertaken in 17 healthy volunteers in which rHuIL-10 was administered as 25 microg/kg s.c. and i.v. doses. Blood samples were collected for 48 hr after dosing to determine serum IL-10 concentrations. Inhibitory activity of IL-10 on ex vivo production of inflammatory cytokines (TNF-alpha and IL-1beta) by LPS-treated peripheral blood cells were measured over 96 hr. RESULTS: A physiologically-relevant modeling approach was developed to determine the pharmacokinetics for two routes of administration (s.c. and i.v.). The i.v. dose showed polyexponential disposition with CL of 65 mL/kg/hr, Vss of 70 mL/kg, and t1/2 of 1.94 hr. Absolute bioavailability averaged 42% for s.c. dosing which produced lower but sustained concentrations. Substantial and prolonged suppression of TNF-alpha and IL-1beta production was achieved during IL-10 treatment. The Hill Function was used to account for the joint concentration-dependent immunosuppressive action of rHuIL-10 after both i.v. and s.c. doses. The IC50 values were about 0.03 ng/ml and Imax values were about 0.85 for both TNF-alpha and IL-1beta suppression. The degree of change as well as the duration of leukocyte response was greater after s.c. administration than after i.v. administration. CONCLUSION: rHuIL-10 shows favorable PKPD characteristics especially by the s.c. route of administration which produced prolonged suppression of cytokine production (ex vivo) which may be applicable in various immune-related disorders.

Cross-Over Studies↗