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Biomedical subjects

W J Jusko

Publications and source records attributed to W J Jusko.

At least 73 records · Page 4Linked to original sources
PubMed1997

Population pharmacokinetics of sirolimus in kidney transplant patients.

OBJECTIVE: To characterize the dose-related pharmacokinetics of the immunosuppressant agent sirolimus (formerly rapamycin) in kidney transplant patients by use of two-stage and nonlinear mixed-effect model population methods. METHODS: Patients (n = 36) from three centers (Germany, the United Kingdom, and Sweden) who received steady-state oral doses of cyclosporine (ciclosporin) were assessed after single oral administration of sirolimus at doses of 3, 5, 10, and 15 mg/m2. Plasma and whole blood sirolimus samples were analyzed by a high-performance liquid chromatographic/mass spectrophotometric method. Simultaneous fitting used biexponential functions with intercept/slope or clearance/volume terms, as well as first-order absorption (ka) and a lag-time. RESULTS: The nonlinear mixed-effect model method (P-Pharm) provided a better characterization of sirolimus kinetics, especially for the absorption and distribution phases where fewer data were available per patient. Sirolimus distribution between whole blood and plasma was concentration-independent, with a mean blood/plasma ratio (coefficient of variation) of 30.9 (48.5%). Elimination was not influenced by dose, as shown by estimates of the terminal half-life of 63 hours (27.5%) and apparent oral blood clearance of 8.9 L/hr (38.2%). Sirolimus distribution parameters were influenced by body weight and surface area. Sirolimus was rapidly absorbed, as shown by the absorption lag-time of 0.27 hour (35.1%), and ka of 2.77 hr-1 (48.4%). The concomitant administration of sirolimus and cyclosporine did not reveal any pharmacokinetic interactions. CONCLUSION: This report provides an initial population pharmacokinetics of sirolimus in kidney transplant recipients receiving cyclosporine concurrently. Sirolimus blood and plasma pharmacokinetics were biexponential and linear for doses from 3 to 15 mg/m2. No pharmacokinetic interaction was found between sirolimus and cyclosporine.

Adult↗
PubMed1997

Mathematical formalism for the properties of four basic models of indirect pharmacodynamic responses.

Four basic models for characterizing indirect pharmacodynamic responses were proposed previously and applied using differential equations. These models consider inhibition or stimulation by drug of the production or loss of mediators or response variables. This report develops partially integrated solutions for these models which allow more detailed examination of the roles of model parameters and pharmacokinetic functions in affecting the time course of drug effects. Because of the nonlinear Hill function, the solutions are represented by means of definite integrals containing kinetic and dynamic functions. These solutions allow a qualitative examination, using calculus, of how response is controlled by Dose, IC50 or SC50, Imax or Smax, and kout for drugs exhibiting monotonic or biphasic disposition. Characteristics of the response curves that were identified include shape, maximum or minimum, and changes with the above parameters and time. These relationships, together with simulation studies, provide a fundamental basis for understanding the temporal aspects of the basic indirect response models.

Mathematics↗
PubMed1997

Effect of hematocrit and albumin concentration on hepatic clearance of tacrolimus (FK506) during rabbit liver perfusion.

Tacrolimus is an immunosuppressive agent used for organ transplantation. Studies were performed to examine the influence of different perfusate hematocrits and albumin concentrations on hepatic extraction of tacrolimus. In vitro binding, efflux and influx between red blood cells (RBCs) and buffer or plasma, and rabbit liver perfusion with use of human erythrocytes were studied. In the range of hematocrits from 0.05 to 0.4, plasma concentrations of tacrolimus were not affected by increased albumin content. Increased hematocrit caused decreases in whole blood:plasma (buffer) concentration ratios. The binding capacity of drug with RBCs was independent of hematocrit, with a value of 440 ng/ml of RBCs; the binding affinity was 0.876 ng/ml using plasma or buffer. Diffusion of tacrolimus from RBCs to buffer was rapid with a clearance of 0.940 ml/min, and equilibration was achieved within 2 min. Diffusion in the opposite direction (buffer-RBCs) was slower with a clearance of 0.576 ml/min. In such diffusion studies, plasma produced a greater difference between efflux (1.70 ml/min) and influx (0.276 ml/min) clearances. During liver perfusion, the major factor regulating elimination of tacrolimus was hematocrit. Both well-stirred and parallel-tube models reflected a low extraction ratio drug with values of 0.15 and 0.17 for the 0.05 and 0.2 hematocrits. Intrinsic clearances were 8.43 and 17.44 ml/min for the well-stirred and parallel-tube models. Albumin had a negligible influence on liver extraction of drug. A model-building process of characterizing nonlinear RBC binding, RBC diffusion rates, and liver perfusion parameters allows the complexities of tacrolimus hepatic clearance to be dissected and shows that strong RBC binding can be artificially perceived as causing a high clearance of the drug.

Animals↗
PubMed1996

Disposition decomposition analysis for pharmacodynamic modeling of the link compartment.

An approach based on disposition decomposition analysis (DDA) and the hysteresis minimization principle has been developed for pharmacodynamic modeling. It allows calculation of the mean transit time and the ratio of distribution clearance to biophase distribution volume of drug, and determination of the drug concentration-time function at the biophase (Cb(t)). The proposed method extends the DDA approach to drug distribution to a possibly heterogeneous effect compartment of a generalized pharmacokinetic/pharmacodynamic model. The application of this DDA-dynamics method is demonstrated using published data for pancuronium.

Gastrointestinal Transit↗
PubMed1996

Pharmacokinetics of prednisolone during administration of sirolimus in patients with renal transplants.

The pharmacokinetic interaction of multiple oral doses of sirolimus (rapamycin) and prednisone were evaluated in 40 stable patients with renal transplants receiving concomitant multiple doses of cyclosporine. Nine sirolimus dosage levels from 1 mg/m2/day to 13 mg/m2/day were studied and compared with placebo. Plasma concentrations of prednisone, prednisolone, and cortisol were measured by high-performance liquid chromatography and analyzed by noncompartmental methods. Mean pharmacokinetic values of prednisolone found before sirolimus administration were as follows: peak plasma concentration (Cmax) was 187 ng/mL; time to peak plasma concentration (tmax) was 2.03 hours; rate of reaching peak plasma concentration (Cmax divided by the area under the concentration-time curve [AUC]) was 0.149 hour-1; terminal half-life (t1/2) was 3.60 hours; AUC was 1206 ng.hour/mL; and apparent clearance (Cl/F) was 0.094 L/hour/kg. During the 2 weeks of concomitant administration, prednisolone elimination decreased in relation to sirolimus dosages. These changes were modest, with mean increases of 18% in Cmax and 27% in t1/2 and mean decreases of 27% in Cl/F for the groups receiving 6 mg/m2/day to 13 mg/m2/day. Most patients initially had plasma cortisol concentrations indicative of adrenal suppression. With sirolimus treatment, the Cmax of cortisol did not decrease further, but the AUC (8:00 AM-8:00 PM) values were significantly lower, independent of sirolimus exposure. The AUC for cyclosporine did not correlate with sirolimus and prednisolone exposure. A 2-week course of sirolimus showed a slight pharmacokinetic interaction between sirolimus and prednisolone/prednisone/cortisol in stable patients with renal transplants.

Adult↗
PubMed1996

Oral absorption characteristics and pharmacokinetics of colchicine in healthy volunteers after single and multiple doses.

Colchicine is an antimitotic drug used to treat gout and familial Mediterranean fever. Absolute bioavailability, pharmacokinetics, and absorption characteristics of colchicine after single 1.0-mg doses in oral solution or tablet form or 0.5-mg intravenous doses were compared in 6 subjects. This study was combined with 14 days of multiple-dose administration of 1.0-mg colchicine tablets in 6 subjects. Serial blood samples were collected for 48 hours after administration of single doses and for 120 hours after the last dose in the multiple-dose regimen. Plasma colchicine profiles as measured by radioimmunoassay were analyzed using deconvolution and compartmental methods. After intravenous bolus injection of colchicine, the area under the concentration-time curve (AUC) was 61.2 +/- 12.7 ng.hr/mL, steady-state volume of distribution (Vss) was 419 +/- 95 L, systemic clearance (Cl) was 8.5 +/- 1.8 L/hr, and the terminal half-life (t1/2) was 57.8 +/- 10.7 hours. After oral administration in solution form, peak plasma concentrations (Cmax) of 6.50 +/- 1.03 ng/mL were reached at time (tmax) 1.07 +/- 0.55 hours, with a rate of 0.109 +/- 0.024 hr-1 (Cmax/AUC); bioavailability was 47 +/- 14%. Oral tablets yielded similar Cmax, tmax, and Cmax/AUC values, but AUC was significantly lower. Most participants exhibited a secondary peak within 6 hours of administration, possibly in relation to a second absorption site or enterohepatic recirculation. This second absorption process was significantly longer than the first one, and accounted for a similar amount of colchicine absorbed. From the multiple-dose study, a model including an alteration of colchicine absorption due to possible drug-induced gastrointestinal modifications allowed better determination of steady-state plasma concentrations of colchicine.

Absorption↗
PubMed1996

Characterization of four basic models of indirect pharmacodynamic responses.

Four basic models of indirect pharmacodynamic responses were characterized in terms of changing dose, Imax or Smax, and IC50 or SC50 to examine the effects of these fundamental drug properties on response profiles. Standard pharmacokinetic parameters were used for generating plasma concentration, and response-time profiles using computer simulations. Comparisons to theoretical expectations were made. In all four models, the maximum response (Rmax) (inhibition or stimulation) and the time of its occurrence (TRmax) were dependent on the model, dose, Imax or Smax, and IC50 or SC50 values. An increase in dose or a decrease in IC50 or SC50 by the same factor produced, as theoretically expected, identical and superimposable pharmacodynamic response patterns in each of the models. Some parameters (TRmax, ABEC) were nearly proportional to log dose, while others (Rmax, CRmax) were nonlinear. Assessment of expected response signature patterns as demonstrated in this report may be helpful in experimental designs and in assigning appropriate models to pharmacodynamic data.

Computer Simulation↗
PubMed1996

Oral contraceptive effects on methylprednisolone pharmacokinetics and pharmacodynamics.

OBJECTIVE: Oral contraceptive (OC) steroids alter the disposition of numerous drugs, including corticosteroids. We investigated the pharmacokinetics and pharmacodynamics of methylprednisolone. METHODS: Twelve women (six women used OC steroids and six women did not) received intravenous methylprednisolone (0.6 mg/kg ideal body weight). Methylprednisolone disposition was assessed from plasma concentrations. Pharmacodynamic parameters measured were plasma cortisol, whole blood histamine (reflecting basophils), and blood helper T lymphocytes. RESULTS: Methylprednisolone clearance was significantly decreased in the women who used OC steroids (0.298 versus 0.447 L/hr/kg), resulting in a longer elimination half-life (2.20 versus 1.72 hours). With use of indirect response models, significant differences were observed with the cortisol and basophil responses. A larger value for the concentration that inhibits the zero-order production rate by 50% (0.37 versus 0.11 ng/ml) was observed in the women who used OC steroids for suppression of cortisol secretion, indicating less sensitivity to the suppressive effects of methylprednisolone. Greater net suppression of basophils was observed in the users of OC steroids (area under the response curve, 694 versus 401 ng x hr/ml). No differences were observed for helper T-cell responses. CONCLUSION: OC steroids appear to inhibit methylprednisolone metabolism. However, mixed changes in several responses occur, indicating that women can probably receive similar doses of methylprednisolone irrespective of OC steroid use.

Adult↗
PubMed1996

Liposomal methylprednisolone in rats: dose-proportionality and chronic-dose pharmacokinetics/pharmacodynamics.

PURPOSE: Methylprednisolone (MPL) encapsulated in liposomes (L-MPL) targets the immune system and enhances immunosuppressive activity of the steroid. We performed dose-dependent and chronic dose studies of L-MPL versus MPL. METHODS: Male Lewis rats received 10 mg/kg i.v. bolus doses of L-MPL (Solu-Medrol). Plasma samples were obtained over an 8 day period and MPL concentrations were assayed by HPLC. Immunosuppressive effects were measured as inhibition of ex vivo splenocyte proliferation induced with PHA. RESULTS: Drug concentrations declined in a similar manner over the first few hours following MPL or L-MPL. Free MPL was cleared from plasma by 6 hr, while the same dose of L-MPL resulted in persistence over an 8-day period. Dose-dependent changes in pharmacokinetic parameters were observed for both free and liposomal drug. Increasing the dose from 2 to 10 mg/kg led to increased clearance from 5.9 to 10.5 (MPL) and from 1.8 to 2.3 L/hr/kg (L-MPL). Blastogenesis was suppressed over 5 days with return to the baseline at day 8 (L-MPL); free MPL produced immunosuppression only over 10 hr. Multiple 2 mg/kg i.v. doses of L-MPL versus MPL twice a week produce plasma drug profiles similar to those obtained after single doses, indicating that neither free nor liposomal steroid accumulates in tissues. Liposomes without drug simultaneously administered with MPL caused partial prolongation of plasma steroid half-life (8.4 hr). CONCLUSIONS: These studies clarify factors causing prolonged drug persistence and immunosuppression with L-MPL. Nonlinear disposition, irregular pharmacokinetics, and secondary effects of the liposomes are complicating factors in use of L-MPL.

Analysis of Variance↗
PubMed1996

Synergistic interaction between dehydroepiandrosterone and prednisolone in the inhibition of rat lymphocyte proliferation.

The interaction between dehydroepiandrosterone (DHEA) and prednisolone (PD) in the inhibition of rat lymphocyte proliferation was evaluated. The in vitro proliferative response of splenocytes from male Sprague-Dawley rats stimulated with phytohemagglutinin (PHA) was measured by the incorporation of 3H-thymidine into the DNA. DHEA and PD were added at the initiation of cultures individually and in various molar ratio combinations. The search for synergy, additivity or antagonism between the two compounds was performed by using the median-effect method of Chou and Talalay and Drewinko's statistical analysis. Both compounds individually inhibit the proliferation of PHA-stimulated rat lymphocytes. DHEA with an IC50 value of 13.4 microM was a thousand times less potent than PD which had an IC50 value of 5.4 nM. Synergy was observed between DHEA and PD. The intensity of the interaction appeared to be function of the molar ratio of the two drugs. The association of DHEA and PD could produce enhanced steroid effects in anti-inflammatory therapy.

Animals↗
PubMed1995

Pharmacokinetics and receptor-mediated pharmacodynamics of corticosteroids.

The corticosteroids, such as prednisolone and methylprednisolone, provide diverse antiinflammatory and immunosuppressive effects which typically show responses with slow onset and prolonged duration. This report summarizes modeling efforts which are successful in describing such steroid effects. Clinical effects with such a pattern, including adrenal suppression and altered trafficking of basophils and helper T-cells, can be related to plasma drug concentrations by models containing an inhibition function and differential equations for controlling input and disposition of the response variable. Some responses have circadian-controlled inputs which add time-dependent complexities to the models. Kinetic/dynamic data for several corticosteroid effects yield IC50 values which agree well with receptor KD values. A relationship of linear AUC of effect versus log AUC of steroid in plasma is found with these models over a large range of doses. Gene-mediated effects of corticosteroids are initiated by receptor-binding which causes a cascade effect altering DNA transcription, RNA, mRNA and proteins or enzymes accounting for drug effects. Models for such behavior have been developed in animals for hepatic tyrosine aminotransferase (TAT) enzyme activity. Studies with methylprednisolone formulated in liposomes show tissue sequestration of steroid, prolonged receptor-binding and extended inhibition of splenocyte proliferation. The data and models usually show good correspondence of the AUC of receptor occupancy with the AUC of pharmacologic response.

Animals↗
PubMed1995

Optimizing whole blood lymphocyte proliferation in the rat.

Use of whole blood for lymphocyte proliferation experiments have advantages over the usual isolated lymphocyte procedure. We have systematically optimized methodology for whole blood lymphocyte proliferation in male Sprague-Dawley rats. Both phytohemagglutinin (PHA) and concanavalin A (ConA) stimulate lymphocyte blastogenesis in whole blood. The response of rat lymphocytes to ConA at supra-optimum conditions doubled that of PHA in contrast to what is observed in human lymphocytes. Proliferation rates relate non-linearly to concentrations of both mitogens with profiles showing lag, log and decline phases with increasing concentrations. The effect of incubation period followed a similar pattern with an optimum growth rate at 72 h. Whole blood from adrenalectomized rats gave higher proliferation rates than blood from intact normal rats. Advantages of the technique include: use of as little as 8 microliters of blood for each determination; rats need not be killed, the technique is less cumbersome, less time consuming, and cheaper to carry out than the traditional isolated lymphocyte method.

Adrenalectomy↗
PubMed1995

Third-generation model for corticosteroid pharmacodynamics: roles of glucocorticoid receptor mRNA and tyrosine aminotransferase mRNA in rat liver.

A third-generation pharmacokinetic/pharmacodynamic model was proposed for receptor/gene-mediated corticosteroid effects. The roles of the messenger RNA (mRNA) for the glucocorticoid receptor (GR) in hepatic GR down-regulation and the mRNA for hepatic tyrosine aminotransferase (TAT) induction by methylprednisolone (MPL) were examined. Male adrenalectomized Wistar rats received 50 mg/kg MPL iv. Blood and liver samples were collected at various time points for a period of 18 hr. Plasma concentrations of MPL, free hepatic cytosolic GR densities, GR mRNA, TAT mRNA, and TAT activities in liver were determined. Plasma MPL profile was biexponential with a terminal t1/2 of 0.57 hr. Free hepatic GR density rapidly disappeared from cytoplasm after the MPL dose and then slowly returned to about 60% of starting level after 16 hr. Meanwhile, GR mRNA level fell to 45% of baseline within 2 hr postdosing, and remained at that level for at least 18 hr. The GR down-regulation of GR mRNA and protein turnover rate were modeled. The TAT mRNA began to increase at about 2 hr, reached a maximum at about 5 hr, and declined to baseline by 14 hr. TAT induction followed a similar pattern, except the induction was delayed about 0.5 hr. Pharmacodynamic parameters were obtained by fitting seven differential equations in a piecewise fashion. The cascade of corticosteroid steps were modeled by a series of inductions for steroid-receptor-DNA complex, two intermediate transit compartments, TAT mRNA, and TAT activity. Results indicate that GR mRNA and TAT mRNA are major controlling factors for the receptor/gene-mediated effects of corticosteroids.

Adrenal Cortex Hormones↗
PubMed1995

Tolrestat pharmacokinetic and pharmacodynamic effects on red blood cell sorbitol levels in normal volunteers and in patients with insulin-dependent diabetes.

OBJECTIVES: To examine the effect of diabetes mellitus on the pharmacokinetics of tolrestat and to investigate its effect on red blood cell sorbitol levels according to a new pharmacodynamic model for this class of drugs. METHODS: Single and multiple doses of tolrestat (200 mg/twice a day) were administered to 12 patients with insulin-dependent (type I) diabetes and 12 healthy volunteers in an open parallel trial. RESULTS: Tolrestat disposition was characterized by first-order absorption and biexponential disposition: In normal subjects the terminal disposition half-life (t1/2) was 13 +/- 3 hours (mean +/- SD) and the apparent oral clearance (CL/F) was 48 +/- 9 ml/hr/kg, similar to the values in patients with type I diabetes mellitus (t1/2 = 14 +/- 4 hours; CL/F = 55 +/- 10 ml/hr/kg). Red blood cell sorbitol concentrations, which declined because of tolrestat's inhibition of aldose reductase, were characterized by an indirect-response model including a 50% inhibition constant (IC50) for production of sorbitol by aldose reductase. The removal of sorbitol (kout) was slower in patients with diabetes. The plasma IC50 averaged 2.0 +/- 1.3 micrograms/ml in normal subjects and 2.5 +/- 1.9 micrograms/ml in patients with diabetes. IC50 values expressed in free (unbound) concentrations (fu = 0.64%), which ranged from 12 to 16 ng/ml, were similar to the in vitro IC50 for inhibition of sorbitol accumulation in human red blood cells. CONCLUSIONS: Tolrestat pharmacokinetics were similar in normal subjects and in patients with diabetes; however, the patients with diabetes had higher baseline sorbitol levels (11 versus 5 nmol/ml for normal subjects) and slower sorbitol efflux rates. The proposed biochemically realistic, dynamic model characterized well the red blood cell sorbitol response patterns after administration of single and multiple doses of tolrestat.

Adult↗
PubMed1995

Pharmacokinetics of tacrolimus in liver transplant patients.

OBJECTIVE: To characterize the pharmacokinetics of the immunosuppressive agent tacrolimus (FK 506) in liver transplant patients. METHODS: Patients (n = 16) were assessed during and after 1- to 3-day intravenous infusions followed by a 2-week course of oral dose therapy. Plasma and whole blood data were fitted simultaneously with equations accounting for nonlinear drug binding by red blood cells to generate clearance (CL) and volume of distribution (V). RESULTS: The maximum blood/plasma ratio of tacrolimus was 55.5 +/- 26.8 (SD) and half-life averaged 12.1 +/- 4.7 hours. The CL and V were relatively high based on plasma concentrations (CL, 1.7 L/hr/kg; V, 30 L/kg) and low based on whole blood (CL, 54 ml/hr/kg; V, 0.9 L/kg), with moderate variability (coefficient of variation, 34% to 49%) among the patients. Correlations of plasma CL and V with maximum blood/plasma ratios (ranging from 13 to 114) were strong (r = 0.65 and r = 0.73). Blood binding affects the disposition of tacrolimus, and plasma concentrations are indirectly and inversely related to red cell binding. The oral dose data for tacrolimus yielded a brief absorption lag time (tlag, 0.39 hour), a variable first-order absorption rate constant (ka, 4.5 +/- 3.0 hr-1), and consistent bioavailability (F, 25% +/- 10%). The area under the concentration-time curve versus 12-hour minimum concentration relationships for both whole blood and plasma were nearly linear, confirming the utility of trough values for monitoring drug exposure. CONCLUSION: This study provides pharmacokinetic guidelines for the use of tacrolimus in patients undergoing hepatic transplantation. Nonlinear blood binding is a major source of interpatient variation in the disposition of tacrolimus.

Administration, Oral↗
PubMed1995

Effect of halofantrine and its desbutyl metabolite on lymphocyte proliferation dynamics.

Halofantrine hydrochloride (HF), one of the latest antimalarial agents currently undergoing clinical trials, and its active metabolite, N-desbutylhalofantrine (DHF), were examined for their effects on human and rat lymphocytes. HF has a biphasic concentration-dependent effect on phytohemagglutinin stimulated proliferation of human lymphocytes. Concentrations lower than 2.25 microM enhance, while higher concentrations inhibit proliferation. The IC50 values were 9.4 microM for HF, 4.5 microM for DHF and 14.7 microM for chloroquine. In human lymphocytes, enhanced proliferation was not detected for DHF unlike for HF. Combined achievable plasma concentrations of HF and DHF may sometimes be in the range where reduced lymphocyte proliferation occurs in vitro when based on simple additive dynamics. It remains to be confirmed if malarial treatment with HF leads to reduced T-cell responsiveness to antigenic challenges since HF and DHF persist for several days.

Adult↗