Pharmacokinetic and pharmacodynamic modelling of the effects of glimepiride on insulin secretion and glucose lowering in healthy humans

Glimepiride is an oral sulfonylurea antihyperglycaemic agent. We used pharmacokinetic-pharmacodynamic (PK-PD) modelling to analyse the relationship between plasma glimepiride concentration, insulin secretion and glucose lowering to determine the effects of the drug in healthy volunteers. A single 2-mg oral dose of glimepiride was administered to six healthy volunteers. The control group received a placebo. All subjects consumed 12 g of sugar immediately after drug administration in order to standardize the initial plasma glucose levels. Serial blood sampling was performed for 9 h after oral dosing. Plasma glimepiride, insulin and glucose levels were determined by validated methods (LC/MS/MS assay, hexokinase method and radioimmunoassay respectively). Time courses of plasma glimepiride concentration, insulin secretion, and glucose lowering effects were analysed by means of PK-PD modelling with the ADAPT II program. The time course of the plasma concentrations followed a two-compartmental model with a lag time. The glimepiride concentration peaked at 191.5 ng/mL at approximately 4 h after administration. The maximal increase in insulin secretion was 9.98 mIU/L and the maximal decrease in plasma glucose was 19.33 mg/dL. Both peak effects occurred at approximately 2.5 h after drug intake. The glucose disappearance model was used to analyse glimepiride's insulin secretion and glucose lowering effects. The PK-PD model described well the relationship between plasma glimepiride and its insulin secretion and hypoglycaemic effects in healthy volunteers.     

Pharmacokinetic and pharmacodynamic modeling of mizolastine in healthy volunteers with an indirect response model

OBJECTIVE: The aim of this work was to model the pharmacokinetic and pharmacodynamic relationship of mizolastine, a new H1-receptor antagonist obtained from histamine-induced wheal and flare inhibition test. METHODS: Fifteen healthy volunteers participated in this double-blind crossover study and randomly received single doses of 5, 10, 15, and 20 mg of mizolastine and placebo at 1 week intervals. Simultaneous histamine tests and blood samples were performed before and at 9 different times up to 24 hours after each dosing. Pharmacokinetic and pharmacodynamic modeling were performed subject by subject for the 4 doses altogether by nonlinear regression. First, plasma concentrations were fit according to a two-compartment open model with zero order absorption and first order elimination. Then an indirect response model with inhibition of the formation rate was developed to describe the pharmacodynamic relationships between flare or wheal raw areas and plasma concentrations with the use of the pharmacokinetic parameters that were previously estimated. RESULTS: Mizolastine dose dependently inhibited the histamine-induced wheal and flare formation with a submaximum effect attained after 10 mg. The mean values of the pharmacodynamic parameters of apparent zero-order rate constant for the flare or wheal spontaneous appearance (k(in)), the first-order rate constant for the flare or wheal disappearance, the mizolastine concentration that produced 50% suppression of the maximum attainable inhibition of k(in), and the maximum attainable inhibition of the effect production were 14.1 cm2/h (coefficient of variation [CV], 32%), 0.68 h(-1) (CV, 24%), 21.1 ng/mL (CV, 77%), and 0.92 (CV, 8%), respectively, for the flare and 1.9 cm2/h (CV, 64%), 0.63 h-1 (CV, 39%), 43.9 ng/mL (CV, 68%), and 0.87 (CV, 12%), respectively, for the wheal inhibition. CONCLUSION: Pharmacokinetic and pharmacodynamic relationships of mizolastine were reliably described with the use of an indirect pharmacodynamic model; this led to an accurate prediction of the pharmacodynamic activity of mizolastine.     

Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans

BACKGROUND: SB 249417 is a humanized anti-factor IX/IXa antibody that, on administration to rats and monkeys, produces an immediate suppression of factor IX activity and prolongation of activated partial thromboplastin times (aPTT). OBJECTIVE: Our objective was to establish the pharmacokinetics of SB 249417 and to explore its effects on factor IX activity levels and aPTT in humans. METHODS: In this phase I, single-blind, randomized, placebo-controlled, parallel-group, single intravenous infusion study, individual and mean data from a total of 26 healthy volunteers at 5 dosing levels were analyzed. A 2-compartment pharmacokinetic model was used in the analysis of total SB 249417 concentration-time profiles. A modified indirect-response model was used, with the total concentration indirectly serving as the driving force for the suppression of free factor IX concentration (as assessed by factor IX activity). The aPTT was related to factor IX activity with a biexponential equation, and a population approach was used to generate posterior parameter estimates for the individual fittings. RESULTS: Mean parameter estimates from individual fittings are 0.092 L/kg for volume of distribution, 0.15 L/kg for steady-state volume of distribution, and 0.0021 L/kg per hour for systemic clearance. The model described well the factor IX activity and aPTT time course in response to SB 249417 at 5 dose levels. The estimated half-life of factor IX in blood was 21 hours. CONCLUSIONS: This model was stable and robust in fitting both mean and individual data. Endogenous factor IX baseline levels and dose were the major determinants of the decline in factor IX activity during the infusion period. Thereafter the recovery of factor IX activity was governed solely by the endogenous factor IX turnover rate.     

Pharmacokinetic/pharmacodynamic modeling of antipyretic and anti-inflammatory effects of naproxen in the rat

Pharmacokinetic/pharmacodynamic modeling was used to characterize the antipyretic and anti-inflammatory effects of naproxen in rats. An indirect response model was used to describe the antipyretic effects of naproxen after short intravenous infusions. The model assumes that basal temperature (T(a)) is maintained by the balance of fever mediators given by a constant (zero order) rate of synthesis (K(syn)), and a first order rate of degradation (K(out)). After an intraperitoneal injection of lipopolysaccharide, the change in T(a) was modeled assuming an increase in fever mediators described as an input rate function [IR(t)] estimated nonparametrically. An inhibitory E(max) model adequately described the inhibition of IR(t) by naproxen. A more complex model was used to describe the anti-inflammatory response of oral naproxen in the carrageenin-induced edema model. Before carrageenin injection, physiological conditions are maintained by a balance of inflammation mediators given by K(syn) and K(out) (see above). After carrageenin injection, the additional synthesis of mediators is described by IR(t) (see above). Such mediators induced an inflammatory process, which is governed by a first order rate constant (K(IN)) that can be inhibited by the presence of naproxen in plasma. The sigmoidal E(max) model also well described the inhibition of K(IN) by naproxen. Estimates for IC(50) [concentration of naproxen in plasma eliciting half of maximum inhibition of IR(t) or K(IN)] were 4.24 and 4.13 microg/ml, for the antipyretic and anti-inflammatory effects, respectively.     

Pharmacokinetic and pharmacodynamic interactions between diltiazem and methylprednisolone in healthy volunteers

OBJECTIVES: The pharmacokinetics and pharmacodynamics after administration of methylprednisolone alone, diltiazem alone, and both drugs jointly were assessed in healthy volunteers. METHODS: An unblinded, controlled, fixed-sequence, 2-period study was carried out in 5 healthy white men who received a single dose of intravenous methylprednisolone, 0.3 mg/kg, on day 2, followed by diltiazem alone, 180 mg, on days 5, 6, and 7, with joint dosing of both drugs on day 8. Methylprednisolone and diltiazem disposition was assessed from plasma concentrations. Pharmacodynamic factors were assessed by plasma cortisol and T-helper and T-suppressor lymphocytes by means of extended indirect response models. RESULTS: The clearance of methylprednisolone was significantly reduced in the presence of diltiazem (25.2 L/h versus 16.8 L/h), resulting in a longer half-life (2.28 hours versus 3.12 hours) and increased area under the plasma concentration-time curve (AUC) (871 ng x h/mL versus 1299 ng x h/mL). The AUC of diltiazem was unchanged in the presence of methylprednisolone. No significant intrinsic pharmacodynamic differences were observed for methylprednisolone versus methylprednisolone-diltiazem. The 50% inhibitory concentration values were 0.446 ng/mL versus 0.780 ng/mL for cortisol, 9.20 ng/mL versus 10.7 ng/mL for T-helper cells, and 18.5 ng/mL versus 20.9 ng/mL for T-suppressor cells (P >.05). Greater net suppression, as indicated by the area between the effect curve and suppression ratios, was observed for the methylprednisolone-diltiazem combination versus methylprednisolone alone, which was attributed to reduced elimination of methylprednisolone. CONCLUSIONS: Controlled-delivery diltiazem, 180 mg, significantly increased methylprednisolone AUC and half-life and reduced clearance, lending to greater systemic exposure to the steroid. However, significant differences between 50% inhibitory concentration values for methylprednisolone when given alone and for methylprednisolone in combination with diltiazem were not seen, which implies no change in cortisol or cell-trafficking sensitivity in the presence of diltiazem.     

Pharmacokinetic and pharmacodynamic modeling of cetrorelix, an LH-RH antagonist, after subcutaneous administration in healthy premenopausal women

PURPOSE: The purpose of this study was the development of pharmacokinetic and pharmacodynamic models for the luteinizing hormone (LH) suppression and subsequent shift in LH surge and follicle-stimulating hormone by cetrorelix in women. BACKGROUND: Cetrorelix is a potent luteinizing hormone-releasing hormone (LH-RH) antagonist and is used for the prevention of the premature ovulation indicated by an LH surge in in vitro fertilization. The pharmacokinetic and pharmacodynamic relationship for the suppression and the shift in the LH surge has not yet been established. METHODS: In a placebo-controlled study, single subcutaneous doses of 1, 3, and 5 mg of cetrorelix were given to 36 subjects on day 8 of the natural menstrual cycle. Cetrorelix, LH, follicle-stimulating hormone, estradiol, and progesterone were determined. RESULTS: Cetrorelix pharmacokinetics were described by a 2-compartment model with a terminal half-life of 56.9 +/- 27.1 hours. Mean shift in LH surge was by 4.1, 7.5, and 9.3 days with the 1-, 3-, and 5-mg doses, respectively. An indirect response sigmoid Emax model was developed for the suppression of LH and the shift in the LH surge. The inhibitory concentration of 50% (for LH suppression) and median effective concentration (for surge shift) estimates were 3.6 ng/mL and 1.6 ng/mL, respectively. The suppression of follicle-stimulating hormone was described by a similar Emax model, with an inhibitory concentration of 50% of 7.25 ng/mL. CONCLUSIONS: A pharmacokinetic and pharmacodynamic model was developed for the transient initial suppression of LH and the subsequent shift in the LH surge after 3 single subcutaneous doses of cetrorelix without ovarian stimulation. A separate model was developed for the suppression of follicle-stimulating hormone by cetrorelix. The shift in the LH surge could be adequately described by the model.     

Pharmacokinetic and pharmacodynamic actions of enalapril in humans: effect of probenecid pretreatment

The pharmacokinetic and pharmacodynamic profiles of oral enalapril (20 mg), in absence and in presence of probenecid pretreatment (1 g twice daily for 5 days), were investigated in 12 healthy volunteers on normal salt intake (150 mmol/24 hr). Mean peak serum concentration of enalapril rose from 158 +/- 7 to 216 +/- 1 ng/ml (P less than .01), whereas that of its metabolite, enalaprilat, rose from 62 +/- 6 to 84 +/- 8 ng/ml (P less than .01) in the presence of probenecid pretreatment. Area under the curve of both enalapril and enalaprilat increased by 50% (P less than .001), which was accompanied by a reduction in renal excretion of both compounds. The renal clearance of enalapril decreased from 229 +/- 19 to 61 +/- 4 ml/min (P less than .001) and that of enalaprilat from 108 +/- 4 to 66 +/- 2 ml/min (P less than .001). The total drug recovery fell from 48 +/- 3 to 38 +/- 2% (P less than .01) of the administered dose with no accompanying changes in plasma elimination half-lives of the parent drug or metabolite. The pharmacodynamic response of enalapril such as fractional excretions of sodium, calcium, magnesium and urate were enhanced by probenecid pretreatment. Absolute urinary excretion of sodium increased from 51 +/- 5 to 91 +/- 8 mmol/6 hr (P less than .001) after enalapril and from 55 +/- 4 to 113 +/- 13 mmol/6 hr (P less than .01) after enalapril in presence of probenecid pretreatment, despite a significant decrease in the renal excretion of enalapril and enalaprilat over the same interval.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetic and pharmacodynamic modeling of exendin-4 in type 2 diabetic Goto-Kakizaki rats

The pharmacokinetics (PK) and pharmacodynamics (PD) of exendin-4 were studied in type 2 diabetic Goto-Kakizaki rats after single doses at 0.5, 1, 5, or 10 μg/kg by intravenous administration and 5 μg/kg by subcutaneous administration. Plasma exendin-4, glucose, and insulin concentrations were determined. A target-mediated drug disposition model was used to characterize the PK of exendin-4. Glucose turnover was described by an indirect response model, with insulin stimulating glucose disposition. Insulin turnover was characterized by an indirect response model with a precursor compartment. After intravenous doses, exendin-4 rapidly disappeared from the circulation, whereas it exhibited rapid absorption (T(max) = 15-20 min) and incomplete bioavailability (F = 0.51) after the subcutaneous dose. Exendin-4 increased insulin release at 2 to 5 min with capacity S(max) = 6.91 and sensitivity SC?? = 1.29 nM, followed by a rebound at 10 to 15 min and a slow return to the baseline. Glucose initially declined because of enhanced insulin secretion, and then gradually increased because of the activation of the neural system by exendin-4. The hyperglycemic action was modeled with increased hepatic glucose production with a linear factor S(RC) = 0.112 1/nM. The mechanistic PK/PD model satisfactorily described the disposition and effects of exendin-4 on glucose and insulin homeostasis in type 2 diabetic rats.     

Pharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections

The pharmacokinetics and pharmacodynamics of linezolid have been extensively investigated in laboratory models, healthy volunteers and patients. Three formulations exist: an intravenous (iv) form, film-coated tablets and an oral suspension. Linezolid can be assayed in serum and body fluids by HPLC and has good bioavailability with a Cmax at 0.5-2 h. The protein binding is 31%, and the volume of distribution is 30-50 L with adequate to good tissue penetration into skin blister fluids, bone, muscle, fat, alveolar cells, lung extracellular lining fluid and CSF. There are two major metabolites of linezolid (PNU-142586 and PNU-142300). Non-enzymic formation of PNU-142586 is the rate-limiting step in the clearance of linezolid, and linezolid and its two main metabolites plus several minor ones are all excreted in the urine. Dose linearity is evident in the Cmax and AUC across a wide range of doses. Gender and age have little effect on pharmacokinetics, but children have greater plasma clearance and volume of distribution and hence, have lower serum concentrations for equivalent doses in adults. No dose modification is needed in mild to moderate liver disease or any degree of renal impairment; however, both PNU-142586 and PNU-142300 accumulate in renal failure. Linezolid is bacteriostatic with a significant post-antibiotic effect against the key pathogens. In animal models of infection, the time the antibiotic concentration exceeds the MIC (t > MIC) helps to determine outcome, and a t > MIC of 40% is predictive of a bacteriostatic effect for both staphylococci and pneumococci. In man, t > MIC and AUC/MIC have been related to bacteriological and clinical outcomes. AUC and length of treatment are also related to the risk of thrombocytopenia.     

Population pharmacokinetic and pharmacodynamic modeling of evobrutinib in healthy adult participants

Evobrutinib, a Bruton''s tyrosine kinase (BTK) inhibitor, has shown therapeutic potential in relapsing multiple sclerosis. This analysis aimed to develop pharmacokinetic (PK) and pharmacodynamic (PD; BTK occupancy [BTKO]) models of evobrutinib and simulate PK and BTKO profiles under alternative dosing regimens. Data were obtained from two phase I evobrutinib studies in healthy adult participants (Japanese and non‐Japanese). Overall, 2326 observations were available from 76 participants; n = 42 from Study MS200527_0017 Part A received evobrutinib 25, 75, or 200 mg once‐daily oral doses for 6 days while fasted; n = 18 from Study MS200527_0019 and n = 16 from Study MS200527_0017 Part B received single evobrutinib 75 mg oral doses with food (low‐fat meal) and while fasted. Population PK/PD modeling for evobrutinib concentrations and BTKO (fraction unbound) were performed using nonlinear mixed‐effects modeling. The effect of once‐daily/twice‐daily regimens and doses of 10–200 mg on BTKO were simulated. A two‐compartment model with sequential zero‐first order absorption and first‐order elimination adequately described the data. Bioavailability increased by 49% with food compared with when fasted. There was no difference in PK parameters between Japanese and non‐Japanese participants. The BTKO profile of evobrutinib was described by the irreversible binding population model. The simulated percentage of participants with minimum BTKO increased in a dose‐dependent manner across the BTKO thresholds of interest (70%, 80%, 90%, and 95% occupancy). Evobrutinib doses of 25 mg once‐daily, 50 mg twice‐daily, or 75 mg twice‐daily while fasted are possible choices for further development, assuming BTKO ≥70% at trough is needed to achieve efficacy.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Evobrutinib is a Bruton''s tyrosine kinase (BTK) inhibitor that impacts a range of key cell types involved in the pathogenesis of multiple sclerosis, such as B cells and myeloid cells, including macrophages and microglia. As evobrutinib binds BTK irreversibly, it provides prolonged target inhibition and, therefore, may be suitable for the chronic treatment of autoimmune diseases.

• WHAT QUESTION DID THIS STUDY ADDRESS?

The aim of this analysis was to develop a population pharmacokinetic model using data from clinical studies, to describe evobrutinib plasma concentration–time data in participants under different conditions and dosing regimens. In addition, the current analysis aimed to develop a pharmacodynamic model to describe the BTK occupancy (BTKO) profile of evobrutinib, to determine dosing regimens achieving the target occupancy necessary for efficacy, based on preclinical experiments.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

A two‐compartment model with sequential zero‐first order absorption and first‐order elimination was able to describe the observations obtained from participants treated under different conditions and at different dose levels. The bioavailability of evobrutinib increased by 49% with food compared with when fasted. The simulated percentage of participants with minimum BTKO increased in a dose‐dependent manner across the BTKO thresholds of interest (70%, 80%, 90%, and 95% occupancy).

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The simulated percentage of participants with minimum BTKO increased in a dose‐dependent manner across the BTKO thresholds. Assuming BTKO ≥70% at trough is needed to achieve efficacy in the different indications considered, the results suggest that daily doses of evobrutinib 25 mg once‐daily, 50 mg twice‐daily, or 75 mg twice‐daily while fasted are plausible choices for further development.     

Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after intravenous and subcutaneous administration in rats

The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEPO) were studied in rats after single i.v. and s.c. administration at three dose levels (450, 1350, and 4050 IU/kg). The plasma concentrations of rHuEPO and its erythropoietic effects including reticulocyte (RET), red blood cell (RBC), and hemoglobin (Hb) levels were determined. A two-compartment model with dual input rate and nonlinear disposition was used to characterize the PK of rHuEPO. The catenary indirect response model with several compartments reflecting the bone marrow and circulating erythropoietic cells was applied. The s.c. doses exhibited slow absorption (T(max) = 12 h) and incomplete bioavailability (F = 0.59). In placebo groups, RBC and Hb values gradually increased over time with growth of the rats, and the changes in the baselines monitored from 8 to 32 weeks of age were described by a nonlinear growth function. All doses resulted in dose-dependent increases in RET counts followed by an immediate decline below the baseline at around 6 days and returned to the predose level in 21-24 days after dosing. A subsequent steady increase of RBC and Hb levels followed and reached peaks at 6 days. A tolerance phenomenon observed at all dose levels was modeled by a negative feedback inhibition with the relative change in Hb level. The PK/PD model well described the erythropoietic effects of rHuEPO as well as tolerance, thereby yielding important PD parameters (S(max) = 1.87 and SC(50) = 65.37 mIU/ml) and mean lifespans of major erythropoietic cell populations in rats.     

Pharmacokinetic/pharmacodynamic modeling of renin biomarkers in subjects treated with the renin inhibitor aliskiren

A semimechanistic pharmacokinetic/pharmacodynamic (PK/PD) model was developed to evaluate the effects of aliskiren on the renin-angiotensin system (RAS) in humans. Mean data were extracted from a three-way crossover, placebo-controlled study. Outcome measures included the time-course of plasma renin activity (PRA) and plasma concentrations of aliskiren, active renin (AR), angiotensin I (ANG I), and angiotensin II (ANG II). The disposition of aliskiren may be best described as a two-compartment model with nonlinear elimination and distribution. The four biomarkers of RAS inhibition were co-modeled, and the AR showed a dose-dependent increase after the administration of aliskiren. This effect was described in terms of an indirect stimulatory response model in conjunction with an empirical submodel of functional adaptation. The estimated concentration of aliskiren necessary for producing 50% inhibition of PRA is 0.66 ng/ml, which is similar to in vitro estimates (0.33 ng/ml) after correction for plasma protein binding. The final and reduced models test the current hypothesis that RAS is inhibited by direct renin antagonism, and also provide suitable platforms for future clinical study design and analysis.     

Pharmacokinetic modeling of plasma and intracellular concentrations of raltegravir in healthy volunteers

Raltegravir is a potent inhibitor of HIV integrase. Persistently high intracellular concentrations of raltegravir may explain sustained efficacy despite high pharmacokinetic variability. We performed a pharmacokinetic study of healthy volunteers. Paired blood samples for plasma and peripheral blood mononuclear cells (PBMCs) were collected predose and 4, 8, 12, 24, and 48 h after a single 400-mg dose of raltegravir. Samples of plasma only were collected more frequently. Raltegravir concentrations were determined using liquid chromatography-mass spectrometry. The lower limits of quantitation for plasma and PBMC lysate raltegravir were 2 nmol/liter and 0.225 nmol/liter, respectively. Noncompartmental analyses were performed using WinNonLin. Population pharmacokinetic analysis was performed using NONMEM. Six male subjects were included in the study; their median weight was 67.4 kg, and their median age was 33.5 years. The geometric mean (GM) (95% confidence interval shown in parentheses) maximum concentration of drug (C(max)), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) for raltegravir in plasma were 2,246 (1,175 to 4,294) nM, 10,776 (5,770 to 20,126) nM · h, and 13,119 (7,235 to 23,788) nM · h, respectively. The apparent plasma raltegravir half-life was 7.8 (5.5 to 11.3) h. GM intracellular raltegravir C(max), AUC(0-12), and AUC(0-∞) were 383 (114 to 1,281) nM, 2,073 (683 to 6,290) nM · h, and 2,435 (808 to 7,337) nM · h (95% confidence interval shown in parentheses). The apparent intracellular raltegravir half-life was 4.5 (3.3 to 6.0) h. Intracellular/plasma ratios were stable for each patient without significant time-related trends over 48 h. Population pharmacokinetic modeling yielded an intracellular-to-plasma partitioning ratio of 11.2% with a relative standard error of 35%. The results suggest that there is no intracellular accumulation or persistence of raltegravir in PBMCs.     

Pharmacokinetic and pharmacodynamic profile of ceftobiprole

A new addition to our therapeutic armamentarium against antimicrobial-resistant pathogens is ceftobiprole, a novel broad-spectrum cephalosporin currently undergoing investigation for the treatment of complicated skin and skin structure infections (cSSSIs) and nosocomial pneumonia. Several qualities make ceftobiprole uniquely suited for early empiric use. A major advance from contemporary β-lactams, ceftobiprole has a high affinity for the altered penicillin-binding protein (PBP) 2′ (2a), making it active against methicillin-resistant staphylococci. It also binds avidly to the relevant PBPs of most Gram-positive and Gram-negative pathogens, and is resistant to hydrolysis by many β-lactamases, making it uniquely suited for infections caused by Gram-positive and mixed Gram-negative organisms. This review summarizes the pharmacokinetic and pharmacodynamic profile of ceftobiprole and addresses in detail the population pharmacokinetic and Monte Carlo simulation analyses used to determine the candidate doses for the cSSSI and nosocomial pneumonia phase 3 clinical trials. This review will also address the ability of the selected dosing regimens in providing adequate free drug concentrations in excess of the MICs against a contemporary group of bacterial isolates from a global resistance surveillance study.     

Pharmacokinetic and pharmacodynamic properties of eptifabatide in healthy subjects receiving unfractionated heparin or the low-molecular-weight heparin enoxaparin

BACKGROUND: The rationale for the combined use of glycoprotein (GP) IIb/Illa inhibitors, such as eptifibatide, and antithrombin agents, such as unfractionated heparin (UFH), in patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and those scheduled for percutaneous coronary intervention is based on the fact that these therapies target the complementary pathophysiologic mechanisms responsible for ischemic adverse effects. The results of a recent study indicated that the combination of eptifibatide and enoxaparin is associated with a reduced rate of ischemic adverse effects compared with the combination of eptifibatide and UFH. Therefore, the coadministration of eptifibatide with enoxaparin is an attractive option for the management of patients with NSTE ACS. OBJECTIVE: This study was designed to determine whether the substitution of enoxaparin for UFH, when coadministered with eptifibatide, affects the pharmacokinetic and pharmacodynamic properties of eptifibatide. METHODS: This open-label, crossover study was conducted at the Quintiles Clinical Pharmacology Unit (Lenexa, Kansas). Healthy subjects were sequentially treated with the GP IIb-IIIa inhibitor eptifibatide (180 microg/kg bolus + 2.0 microg/kg.min infusion) plus UFH or eptifibatide plus the low-molecular-weight heparin enoxaparin, on 2 occasions, separated by a 6- to 14-day washout period. The order of administration of the 2 regimens was random. The primary end point of the study was the steady-state plasma concentration of eptifibatide (Css); secondary end points included the inhibition of platelet aggregation, area under the plasma-concentration time curve, apparent volume of distribution, plasma elimination half-life (t 1/2), and total body eptifibatide clearance (Cl). RESULTS: A total of 14 subjects (10 men, 4 women; mean [SD] age, 53.2 [6.0]years) were enrolled. The mean (SD) Css of eptifibatide was essentially identical when it was coadministered with either UFH or enoxaparin (1640 [227] ng/mL and 1610 (229) ng/mL, respectively). In addition, no clinically significant differences were found between the coadministration of UFH versus enoxaparin in platelet aggregation inhibition, t 1/2, eptifibatide Cl, or other pharmacokinetic parameters. Both regimens were well tolerated; no serious adverse effects were reported. CONCLUSION: The results in this population of healthy subjects, age-matched to the intended target population, suggest that eptifibatide can be used in the treatment of NSTE ACS effectively, with good tolerability, and without dose adjustment when coadministered with enoxaparin instead of with UFH.     

Pharmacokinetic/pharmacodynamic modeling of the antinociceptive effects of (+)-tramadol in the rat: role of cytochrome P450 2D activity

In this study the role of cytochrome P450 2D (CYP2D) in the pharmacokinetic/pharmacodynamic relationship of (+)-tramadol [(+)-T] has been explored in rats. Male Wistar rats were infused with (+)-T in the absence of and during pretreatment with a reversible CYP2D inhibitor quinine (Q), determining plasma concentrations of Q, (+)-T, and (+)-O-demethyltramadol [(+)-M1], and measuring antinociception. Pharmacokinetics of (+)-M1, but not (+)-T, was affected by Q pretreatment: early after the start of (+)-T infusion, levels of (+)-M1 were significantly lower (P < 0.05). However, at later times during Q infusion those levels increased continuously, exceeding the values found in animals that did not receive the inhibitor. These results suggest that CYP2D is involved in the formation and elimination of (+)-M1. In fact, results from another experiment where (+)-M1 was given in the presence and in absence of Q showed that (+)-M1 elimination clearance (CL(ME0)) was significantly lower (P < 0.05) in animals receiving Q. Inhibition of both (+)-M1 formation clearance (CL(M10)) and CL(ME0) were modeled by an inhibitory E(MAX) model, and the estimates (relative standard error) of the maximum degree of inhibition (E(MAX)) and IC(50), plasma concentration of Q eliciting half of E(MAX) for CL(M10) and CL(ME0), were 0.94 (0.04), 97 (0.51) ng/ml, and 48 (0.42) ng/ml, respectively. The modeling of the time course of antinociception showed that the contribution of (+)-T was negligible and (+)-M1 was responsible for the observed effects, which depend linearly on (+)-M1 effect site concentrations. Therefore, the CYP2D activity is a major determinant of the antinociception elicited after (+)-T administration.     

Pharmacokinetic and pharmacodynamic variability of fluindione in octogenarians

In the PREPA observational study, we investigated the factors influencing pharmacokinetic and pharmacodynamic variability in the responses to fluindione, an oral anticoagulant drug, in a general population of octogenarian inpatients.Measurements of fluindione concentrations and international normalized ratio (INR ) were obtained for 131 inpatients in whom fluindione treatment was initiated. Treatment was adjusted according to routine clinical practice. The data were analyzed using nonlinear mixed-effects modeling, and the parameters were estimated using MONOLI X 3.2. The pharmacokinetics (PK) of fluindione was monocompartmental, whereas the evolution of INR was modeled in accordance with a turnover model (inhibition of vitamin K recycling). Interindividual variability (II V) was very large. Clearance decreased with age and with prior administration of cordarone. Patients who had undergone surgery before the study had lower IC50 values, leading to an increased sensitivity to fluindione. Pharmacokinetic exposure is substantially increased in elderly patients, warranting a lower dose of fluindione.     

Pharmacokinetic and pharmacodynamic modeling of recombinant human erythropoietin after intravenous and subcutaneous dose administration in cynomolgus monkeys

The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEpo) were investigated in monkeys. A two-compartment model with dual input and nonlinear disposition could adequately characterize the PK of rHuEpo upon three intravenous and six s.c. administrations. The kinetic model suggests rapid zero-order absorption of part of the s.c. dose (35%) followed by a slow first-order entry through the lymphatics. The s.c. treatments caused a delayed dose-dependent rise in reticulocyte numbers peaking between 100 and 200 h and returning to baseline by 300 to 400 h. This was followed by steady rises in red blood cell (RBC) and hemoglobin counts. A physiological catenary model based on a life span concept with rHuEpo stimulating the production of two cell populations (progenitor cells and erythroblasts) was applied. The model could adequately describe the reticulocyte responses upon the various s.c. treatments, giving estimates of maturation times for cells in the various stages of differentiation including the early progenitor cells (70.4 h), erythroblasts (15.0 h), and reticulocytes (141.6 h) that are close to the literature reported values. An Smax of 3.13 was estimated indicating a moderate maximum stimulation of erythropoiesis, whereas the SC50 was 842 IU/l. The model was used to effectively predict the increases in RBC and hemoglobin counts as well. In conclusion, the physiological PK/PD model developed could adequately describe the time course of rHuEpo effects, yielding realistic estimates of cell life span parameters.     

Pharmacokinetic and pharmacodynamic study of three products of epoetin alfa as single subcutaneous dose in healthy volunteers

Hemax® is an epoetin alfa product developed by Biosidus S.A. in Argentina at the end of the 1980s and has been present in that market since 1991. The initial presentation was a lyophilized powder containing albumin as stabilizer, to best adapt to environmental conditions in developing countries; more recently, a prefilled syringe, albumin-free presentation was developed, since this presentation has become the preferred standard in many markets. The primary objective was to compare the pharmacokinetic profile of different formulations of epoetin alfa after a single subcutaneous administration to healthy volunteers of 40 000 IU of Eprex/Erypo® and Hemax® PFS. This clinical trial was conceived following an open-label, randomized, three-way three-period cross-over balanced, and sequential design. The study was conducted on 24 healthy volunteers. To analyze similarity between Hemax® PFS and the innovator product, Eprex®, area under the curve (AUC) and C_max of both products have been compared. The 90% CI lower limit for the geometric mean ratios was higher than 80% for any comparisons, and the 90% CI upper limit for these geometric ratios was below 125% for all the comparisons made, thus demonstrating equivalence between both products. The comparison between Hemax® PFS and Eprex® resulted in similar 90% CI for C_max, AUC_{(0–120 h)} and AUC_(0-inf) ratios, all of them within the 80–125% interval, with a power above 95% for each ratio. These findings suggest biosimilar patterns for absorption velocity (with T_max close to 15 h), absorption extent, and elimination (with an elimination half-life close to 25–30 h for each formulation).     

Pharmacokinetic basis of the antiplatelet action of prasugrel

Prasugrel is the most recent development of thienopyridine-type antiplatelet drugs. Like the earlier-generation thienopyridines, i.e. ticlopidine and clopidogrel, prasugrel is also an inactive prodrug that requires metabolic processing in vivo to generate the active antiplatelet metabolite. The efficacy of this bioactivation is the key determinant for the pharmacodynamic potency of the compound, i.e. the irreversible blockade of the platelet P2Y12-ADP receptor. Prasugrel is rapidly absorbed from the gut. After oral administration of standard-loading doses of 60 mg, maximum plasma levels of the active metabolite are achieved within 1 h, effective, maximum inhibition of platelet aggregation at 1-2 h. Bioconversion of prasugrel into the active metabolite requires two metabolic steps that occur in sequence. The first is the generation of a thiolactone-intermediate, mainly by carboxyesterases-2 in the intestine, the second the cytochrome (CYP)-dependent conversion of the thiolactone into the active metabolite. This second step involves several cytochromes, most notably CYP3A4, CYP2C19, CYP2B6, and CYP2C9. The enzymatic generation of the active metabolite of prasugrel is much more effective than that of clopidogrel where only about 5% of oral clopidogrel is transformed into the active compound by two-step CYP-dependent procedures. About 70% of prasugrel metabolites are excreted in the urine and 30% in the feces. The molar potency of the respective active metabolites of prasugrel and clopidogrel is identical. Thus, the more rapid onset, higher potency and lower interindividual variability of antiplatelet effects of prasugrel as compared to clopidogrel in vivo are entirely because of its more efficient pharmacokinetics.