PK PD Research Articles

Highlights of This Issue

Lee and colleagues examined serial measurements of cholesterol, triglycerides, and glucose from patients randomized to interferon or temsirolimus in the Global Advanced Renal Cell Carcinoma Phase III Trial. Temsirolimus treatment was associated with larger mean increases in cholesterol (1.02 mmol/L; P < 0.0001), triglycerides (0.32 mmol/L; P = 0.0008), and glucose (1.28 mmol/L; P < 0.0001) compared with interferon, and improved survival (OS: HR 0.76, P = 0.02; PFS: HR = 0.70; P = 0.001). Cholesterol increase is a potential predictor for temsirolimus efficacy; these data have important implications for the design of other mTOR inhibitor studies.Erythropoiesis-stimulating agents (ESA) are widely used in treatment of myelodysplastic syndromes (MDS). Their efficacy is variable, and clinical parameters may only partially predict response. To refine prediction of response, Spinelli and colleagues set up a cytofluorimetric assay to evaluate in vitro activation of the erythropoietin signaling pathway in primary MDS marrow cell subpopulations. Erythropoietin in vitro was able to phosphorylate STAT5 in erythroid progenitors of MDS. This activation was significantly weaker than in progenitors from normal marrows, but correlated with clinical response. This test successfully identifies, prior to therapy, MDS patients who will respond to ESAs, thus avoiding noneffective treatments.GDC-0973 is a potent and selective MEK1 inhibitor currently in clinical trials. Wong and colleagues designed a series of preclinical studies to characterize GDC-0973 tumor disposition and pharmacodynamics in preclinical melanoma tumor models. PK–PD modeling was used to integrate preclinical and limited early clinical data in order to identify a minimum target plasma concentration in patients. Prospective predictions of active doses compared well with clinical responses. This work illustrates how PK–PD modeling can be used to improve the predictive value of preclinical data in the phase I setting.Demetri and colleagues present the complete longitudinal analyses, including final overall survival (OS), from the randomized, placebo-controlled, phase III study that led to regulatory approval of sunitinib for the treatment of patients with advanced imatinib-resistant/intolerant gastrointestinal stromal tumor. The confounding effect of the study's crossover design (allowing placebotreated patients to receive sunitinib upon disease progression) on OS was demonstrated: Conventional analyses resulted in biased comparisons favoring the control arm, despite a statistically significant difference in time to tumor progression. However, rank-preserving structural failure-time analysis modeling the absence of crossover estimated a substantial OS benefit for sunitinib versus placebo.

MLN9708, an investigational proteasome inhibitor, in patients (pts) with solid tumors: Updated phase I results.

e13603 Background: MLN9708 is a potent, reversible, orally bioavailable, and specific 20S proteasome inhibitor. This study (NCT00830869) assessed the safety, MTD, PK, PD, and antitumor activity of intravenous (IV) MLN9708 in pts with solid tumors. Methods: Pts aged ≥18 yrs (ECOG PS 0–2) received increasing doses of IV MLN9708 (starting at 0.125 mg/m2) on days 1, 4, 8, and 11 of 21-day cycles, for up to 12 cycles. MTD expansion cohorts included head and neck (H&N) cancer, non-small cell lung cancer, soft tissue sarcoma, prostate cancer, and a tumor PD expansion cohort. Plasma PK and blood PD data were analyzed by a non-compartmental method using WinNonlin software v5.3. The candidate PD biomarker ATF-3 was assessed using IHC. Results: 113 pts were enrolled; 23 in dose escalation and 96 in MTD expansion (includes 6 from dose escalation) cohorts. Median age of these heavily pretreated pts was 58 yrs (range 29–80). MTD was established as 1.76 mg/m2. Pts have received a median of 2 cycles (range 1–12) to date (data cut-off Dec 1, 2011); 22 received ≥4 cycles. 88% had ≥1 drug-related AE; most common drug-related AEs included fatigue (40%), thrombocytopenia (39%), rash (high level term) (33%), and nausea (32%). 52% of pts experienced grade ≥3 drug-related AEs, including thrombocytopenia (20%) and rash (9%). Drug-related peripheral neuropathy (PN) was seen in 13% of pts; 2 pts had grade 3 PN. 25% had drug-related SAEs, 15% discontinued due to AEs; 7 pts died, all unrelated to treatment. Of 75 response-evaluable pts, 26 achieved SD. A partial response (PR) was observed in a pt in the H&N cohort; response was achieved after 4 cycles and maintained through 8 cycles. Change in ATF-3 levels in tumor tissue post treatment was seen in 6 patients with tumor biopsy samples, indicating proteasome inhibition. PK data showed three-exponential plasma disposition, half-life of ~4–8 days, and dose linearity from 0.5–2.34 mg/m2. At MTD, maximal 20S proteasome inhibition in blood was approximately 60% at 0.08 hours. Whole blood PD effect was immediate and dose dependent. Conclusions: These data suggest that twice-weekly IV MLN9708 has a generally manageable safety profile and potential clinical utility; updated results will be presented.

An agenda for UK clinical pharmacology: Monitoring drug therapy

Drug development has improved over recent decades, with refinements in analytical techniques, population pharmacokinetic–pharmacodynamic (PK–PD) modelling and simulation, and new biomarkers of efficacy and tolerability. Yet this progress has not yielded improvements in individualization of treatment and monitoring, owing to various obstacles: monitoring is complex and demanding, many monitoring procedures have been instituted without critical assessment of the underlying evidence and rationale, controlled clinical trials are sparse, monitoring procedures are poorly validated and both drug manufacturers and regulatory authorities take insufficient account of the importance of monitoring.Drug concentration and effect data should be increasingly collected, analyzed, aggregated and disseminated in forms suitable for prescribers, along with efficient monitoring tools and evidence‐based recommendations regarding their best use. PK–PD observations should be collected for both novel and established critical drugs and applied to observational data, in order to establish whether monitoring would be suitable. Methods for aggregating PK–PD data in systematic reviews should be devised.Observational and intervention studies to evaluate monitoring procedures are needed. Miniaturized monitoring tests for delivery at the point of care should be developed and harnessed to closed‐loop regulated drug delivery systems. Intelligent devices would enable unprecedented precision in the application of critical treatments, i.e. those with life‐saving efficacy, narrow therapeutic margins and high interpatient variability.Pharmaceutical companies, regulatory agencies and academic clinical pharmacologists share the responsibility of leading such developments, in order to ensure that patients obtain the greatest benefit and suffer the least harm from their medicines.

Mucoadhesive nanoparticles for prolonged ocular delivery of natamycin: In vitro and pharmacokinetics studies

The aim of this study was to prepare natamycin encapsulated lecithin/chitosan mucoadhesive nanoparticles (NPs) for prolonged ocular application. These NPs were characterized by their mean particle size 213nm, encapsulation efficiency 73.57%, with a theoretical drug loading 5.09% and zeta potential +43. In vitro release exhibited a biphasic drug release profile with initial burst followed by a very slow drug release. The MIC90 and zone of inhibition of NPs showed similar antifungal activity as compared to marketed suspension and free natamycin against Candida albicans and Aspergillus fumigates. The ocular pharmacokinetics of NPs and marketed formulation were evaluated in NZ rabbits. The NPs exhibit significant mucin adhesion. The AUC(0−∞) was increased up to 1.47 fold and clearance was decreased up to 7.4-fold as compared to marketed suspension. The PK–PD and pharmacokinetic simulation was carried out to estimate optimum dosing regimen for good efficacy. Thus, lecithin/chitosan NPs could be considered useful approach aiming to prolong ocular residence and reduce dosing frequency.

The utility of pharmacokinetic–pharmacodynamic modeling in the discovery and optimization of selective S1P1 agonists

Sphingosine-1-phosphate (S1P1) receptor agonists such as Fingolimod (FTY-720) are a novel class of immunomodulators that have clinical utility in the treatment of remitting relapsing multiples sclerosis. This class of compound act by inducing peripheral lymphopenia.Using an integrated pharmacokinetic/pharmacodynamic (PK–PD) approach based on an in vivo rat model, novel S1P1 agonists were identified with a predicted more rapid rate of reversibility of lymphocyte reduction in human compared to Fingolimod.The in vivo potency of 15 compounds based on PK–PD modelling of the rat lymphocyte reduction model was correlated with in vitro measures of potency at the S1P1 receptor using β arrestin recruitment and G-protein signalling.A structurally novel S1P1 agonist was identified and predictions of human pharmacokinetics and clinical dose are presented.

Mechanism-based model characterizing bidirectional interaction between PEGylated liposomal CKD-602 (S-CKD602) and monocytes in cancer patients

S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic–pharmacodynamic (PK–PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK–PD models were developed and fit simultaneously to the PK–PD data, using NONMEM®. The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis–Menten kinetics in the myelosuppression-based model. The mechanism-based PK–PD model characterized the nonlinear PK disposition, and the bidirectional PK–PD interaction between S-CKD602 and monocytes.

Pharmacokinetic and pharmacodynamic properties of carvedilol in fructose hypertensive rats

Cardiovascular effects and pharmacokinetics of carvedilol were assessed in fructose-fed rats using pharmacokinetic–pharmacodynamic (PK–PD) modeling.Male Sprague–Dowley rats were randomly assigned to receive tap water (C rats) or fructose solution (10% w/v) (F rats) during 6 weeks. Effects of carvedilol (1–3 mg/kg i.v.) on blood pressure, heart rate and blood pressure variability were recorded. Carvedilol plasma pharmacokinetics was studied by traditional blood sampling. Relationship between carvedilol concentrations and their hypotensive and bradycardic effects was established by PK–PD modeling. Vascular sympatholytic activity of carvedilol was assessed by estimation of drug effects on low frequency blood pressure variability using spectral analysis.A greater volume of distribution and clearance of S-carvedilol compared to R-enantiomer was found in both experimental groups. Although PK–PD properties of S-carvedilol chronotropic effect were not altered in F rats, hypertensive rats showed greater efficacy to the carvedilol hypotensive response after administration of the higher dose. A similar potency of carvedilol to inhibit sympathetic vascular activity was found in F rats.Carvedilol showed enantioselective pharmacokinetic properties with increased distribution in F rats compared with normotensive animals. An enhanced hypotensive activity of carvedilol was found in F rats compared with C rats, which is not related to enhance sympatholytic activity.

Population Analysis of Erlotinib in Adults and Children Reveals Pharmacokinetic Characteristics as the Main Factor Explaining Tolerance Particularities in Children

The aim of this pharmacokinetic-pharmacodynamic (PK-PD) analysis was to evaluate the pharmacologic characteristics of erlotinib and its main metabolite (OSI-420) in pediatric patients compared with those in adult patients. Plasma concentrations of erlotinib and OSI-420 of 46 children with malignant brain tumors included in a phase I study and 42 adults with head and neck carcinoma were analyzed by a population-pharmacokinetic method (NONMEM). The effect of several covariates and single nucleotide polymorphisms (SNP) in ABCB1, ABCG2, and CYP3A5 on pharmacokinetic parameters was evaluated. PK/PD relationships between plasma drug exposure Area Under the Curve (AUC) at day 1 and skin toxicity were studied in children and compared with the relationship observed in adults. A significant difference in erlotinib clearance (P = 0.0001), when expressed in L·h(-1)·kg(-1), was observed between children and adults with mean values of 0.146 and 0.095, respectively (mean difference = 0.051 L·h(-1)·kg(-1), SD = 0.0594). However, a common covariate model was obtained describing erlotinib clearance according to body weight, alanine aminotransferase, ABCB1, and CYP3A5 polymorphisms (2677G > T/A and 6986G > A) for both children and adult patients. The PK-PD relationship was very consistent between the children and adult groups with risk of skin toxicity rising with increasing erlotinib AUC. The nonlinear population approach applied to pharmacokinetic data combined with a pharmacokinetic-pharmacodynamic analysis revealed that the higher recommended dose in children (125 mg/m(2)/day) compared with adults (90 mg/m(2)/day) is mainly due to pharmacokinetic rather than pharmacodynamic particularities.

Mechanism-based pharmacokinetic–pharmacodynamic modeling of the estrogen-like effect of ginsenoside Rb1 on neural 5-HT in ovariectomized mice

We sought to develop a mechanism-based pharmacokinetic–pharmacodynamic (PK–PD) model to characterize the effects of ginsenoside Rb1 (Rb1) and estradiol (E 2) on neural 5-hydroxytryptamine (5-HT) concentration in ovariectomized mice. PK data of Rb1 and E 2 were obtained in plasma and brain. Brain levels of 5-HT, tryptophan (TRP), 5-hydroxytryptophan (5-HTP), and 5-hydroxyindoleacetic acid (5-HIAA) were determined after a single intravenous injection of Rb1 (20 mg/kg) and E 2 (0.2 mg/kg) in ovariectomized mice. The activities of tryptophan hydroxylase (TPH), aromatic amino acid decarboxylase (AAAD), and monoamine oxidase (MAO) were also evaluated. Rb1 and E 2 elevated neural 5-HT levels via TPH activation and MAO inhibition, respectively. Effects were well described by the mechanism-based PK–PD model. The net effect of increased 5-HT induced by MAO inhibition is greater than TPH activation. The increased brain levels of 5-HT induced by Rb1 and E 2 were well described by the present PK–PD model, suggesting the use and further development of this mechanism-based model for the effects of ginsenoside on brain 5-HT levels.

PK–PD Modeling of Protein Drugs: Implications in Assay Development

Pharmacokinetic-pharmacodynamic (PK-PD) modeling is an integral part of the preclinical and clinical development of protein drugs. Bioanalytical data from appropriately selected and well-characterized PK and PD biomarker assays can be incorporated into mechanistic PK-PD models and allow a quantitative relationship between protein drug exposure, target modulation, and biochemical, physiological and pathophysiological effects to be established. The selection of PD biomarkers that assess target engagement and modulation in the extracellular milieu and downstream cellular effects can provide proof-of-mechanism and define the magnitude and duration of target modulation following drug administration. The PK-PD data can provide an important link between magnitude of target modulation and clinical efficacy and safety outcomes, and guide the selection of doses and dosing schedules for clinical trials. In this article, approaches to the selection and development of fit-for-purpose, PK and PD assays for protein drugs are reviewed, and the applications of the assay results in PK-PD models are discussed.

Theoretical optimization of Irinotecan-based anticancer strategies in the case of drug-induced efflux

The anticancer drug Irinotecan (CPT11) is known to trigger the induction of ATP-Binding Cassette (ABC) transporters, responsible for the efflux of the drug and its metabolites outside of the cells. The drug-modulated overexpression of those transporters prevents its accumulation in the intracellular medium, therefore decreasing its efficacy. A critical clinical concern lies in the design of CPT11-based therapeutic strategies which eradicate a maximum number of cancer cells despite their ability to become resistant. In order to address this issue, we supplemented an existing mathematical model of CPT11 molecular pharmacokinetics–pharmacodynamics (PK–PD) with a new model of CPT11-induced overexpression of ABC transporters. We then theoretically optimized exposure to CPT11 given as a single agent or combined either with ABC transporter inhibitors, or with inhibitors of nuclear factors whose activation is responsible for transporter overexpression. We firstly considered a cancer cell population endowed with the ability of inducing their transporters. For any drug combination, we concluded that the highest concentration of CPT11 should be administered in order to kill a maximum number of cancer cells, despite the triggering of resistance. We then considered a population of healthy cells which were assumed to be identical to cancer cells except that they were not able to become resistant. Optimal schemes were defined as the ones which maximized DNA damage in cancer cells under the constraint of DNA damage in healthy cells not exceeding a tolerability threshold. The optimal therapeutic strategy consisted in combining CPT11 with ABC transporter inhibitors as it achieved a complete reversal of resistance by means of the lowest concentrations of CPT11.

What it takes to understand and cure a living system: computational systems biology and a systems biology-driven pharmacokinetics–pharmacodynamics platform

The utility of model repositories is discussed in the context of systems biology (SB). It is shown how such repositories, and in particular their live versions, can be used for computational SB: we calculate the robustness of the yeast glycolytic network with respect to perturbations of one of its enzyme activities and one transport system. The robustness with respect to perturbations in the key enzyme phosphofructokinase is surprisingly large. We then note the upcoming convergence of pharmacokinetics-pharmacodynamics (PK-PD) and bottom-up SB. In PK alone, quite a few one-, two- or more compartment models provide valuable initial guesses and insights into the absorption, distribution, metabolism and excretion of particular drugs. These models are phenomenological however, forbidding implementation of molecule-based tools and network information. In order to facilitate a fruitful synergy between SB and PK-PD, and between PK and PD, we present a new platform that combines standard phenomenological models used in the PK/PD field with mechanism-based SB models and approaches.

Designing simple PK–PD studies in children

Conducting clinical pharmacology research studies in pediatric patients is challenging because of ethical and practical constraints but necessary to ensure that drugs are used safely and effectively in this population. Developments in laboratory analytical techniques, such as improved assay sensitivity and the use of alternative sample matrices, can reduce blood loss and offer less invasive blood sampling, causing less trauma to the patient and fewer ethical concerns. Recent advances in data analysis techniques, which aim to extract the maximum amount of useful information from small sample numbers, should be considered when planning a clinical trial and incorporated into the study design. Using 'population' methodology allows a more flexible sampling strategy that enables valuable data to be collected in the course of routine clinical practice, rather than in a rigid, and potentially artificial, setting. Integration of pharmacokinetics and pharmacodynamics and the application of physiological approaches and simulation techniques to the analysis and interpretation of drug concentration and effect data offer new opportunities that have particular relevance to pharmacological research in the field of pediatric anesthetics.

Population pharmacokinetic–pharmacodynamic modeling of ketamine-induced pain relief of chronic pain

Aims Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic–pharmacodynamic (PK–PD) modeling study on the effect of S(+)-ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Methods Sixty CRPS-1 patients were randomly allocated to received a 100-h infusion of S(+)-ketamine or placebo. The drug infusion rate was slowly increased from 5 mg/h (per 70 kg) to 20 mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11 weeks. A population PK–PD model was developed to analyze the S(+)-ketamine-pain data. Results Plasma concentrations of S(+)-ketamine and its metabolite decreased rapidly upon the termination of S(+)-ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 67 ± 10% and 23 ± 9% (population value ± SE), respectively. The pain data were well described by the PK–PD model with parameters C 50 = 10.5 ± 4.8 ng/ml (95% ci 4.37–21.2 ng/ml) and t½ for onset/offset = 10.9 ± 4.0 days (5.3–20.5 days). Discussion Long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50 days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present.

Fractional dynamics pharmacokinetics–pharmacodynamic models

While an increasing number of fractional order integrals and differential equations applications have been reported in the physics, signal processing, engineering and bioengineering literatures, little attention has been paid to this class of models in the pharmacokinetics–pharmacodynamic (PKPD) literature. One of the reasons is computational: while the analytical solution of fractional differential equations is available in special cases, it this turns out that even the simplest PKPD models that can be constructed using fractional calculus do not allow an analytical solution. In this paper, we first introduce new families of PKPD models incorporating fractional order integrals and differential equations, and, second, exemplify and investigate their qualitative behavior. The families represent extensions of frequently used PK link and PD direct and indirect action models, using the tools of fractional calculus. In addition the PD models can be a function of a variable, the active drug, which can smoothly transition from concentration to exposure, to hyper-exposure, according to a fractional integral transformation. To investigate the behavior of the models we propose, we implement numerical algorithms for fractional integration and for the numerical solution of a system of fractional differential equations. For simplicity, in our investigation we concentrate on the pharmacodynamic side of the models, assuming standard (integer order) pharmacokinetics.

Pharmacokinetics and Pharmacodynamics of a Chimeric/Humanized Anti‐CD3 Monoclonal Antibody, Otelixizumab (TRX4), in Subjects With Psoriasis and With Type 1 Diabetes Mellitus

Otelixizumab is an aglycosylated chimeric/humanized monoclonal antibody (mAb) directed to human CD3epsilon. This report describes population pharmacokinetics/pharmacodynamic (PK/PD) modeling of serum otelixizumab concentrations, changes in CD4+ and CD8+ T-cell counts, and modulation and saturation of CD3/T-cell receptors (TCR) (determined by flow cytometry) after IV administration of otelixizumab in subjects with either type 1 diabetes or psoriasis. Otelixizumab PK were monoexponential with Michaelis-Menten elimination. Nonlinearity was manifested at high concentrations (K(m) = 0.968 microg/mL). Lymphocyte dynamics were captured by an indirect response model simplified to direct inhibition. In diabetic subjects, the otelixizumab serum concentration producing a 50% decrease in peripheral blood counts was 0.0187 microg/mL for CD4+ T cells and 0.0120 microg/mL for CD8+ T cells. Corresponding values for psoriatic subjects were much lower: 0.000533 for CD4+ T cells and 0.000269 microg/mL for CD8+ T cells. Total (sum of unbound and otelixizumab-bound) CD3/TCR was approximately equal to unbound CD3/TCR, suggesting that there were few otelixizumab-(CD3/TCR) complexes at the T-cell surface. Down-modulation of CD3/TCR was described by direct inhibition. Otelixizumab concentrations producing 50% reduction in free CD3/TCR sites was similar for diabetes and psoriasis, 0.0144 and 0.0162 microg/mL. Integrated PK/PD models were successfully applied to assess otelixizumab PK and diverse PD responses.

The role of population PK-PD modelling in paediatric clinical research.

Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK–PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK–PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK–PD parameters with the highest precision. Once a population PK–PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child.

Use of vancomycin pharmacokinetic–pharmacodynamic properties in the treatment of MRSA infections

Vancomycin is a commonly used antimicrobial in patients with methicillin-resistant Staphylococcus aureus (MRSA) infections. Increasing vancomycin MIC values in MRSA clinical isolates makes the optimization of vancomycin dosing pivotal to its continued use. Unfortunately, limited data exist regarding the optimal pharmacokinetic–pharmacodynamic (PK–PD) goal to improve bacterial killing and clinical outcomes with vancomycin. The hallmark study in this area suggests that achieving an AUC to MIC ratio of over 400 improves the likelihood of achieving these outcomes. Challenges in the implementation of PK–PD-based dosing for vancomycin include current methodologies utilized in microbiology laboratories, as well as intra- and interpatient pharmacokinetic variability. Individualized dosing based on MIC and specific patient factors is important to achieve optimal outcomes from vancomycin therapy.

Determination of a dosage regimen of colistin by pharmacokinetic/pharmacodynamic integration and modeling for treatment of G.I.T. disease in pigs

Colistin is an antimicrobial drug of the polymyxin group and COLIVET SOLUTION is an aqueous solution containing colistin sulphate (2 × 10 6 IU/mL), formulated for oral administration. The target species is the pig, particularly the suckling and post weaning animal. This investigation was undertaken to provide pharmacokinetic and pharmacodynamic data on which to base the selection of dosage rate and interval of the solution for the treatment of porcine colibacillosis. Colistin absorption from the gastrointestinal tract of young pigs, when administered at dosage rates of 25,000, 50,000 and 1,00,000 IU/kg, was slight or absent. The drug was therefore restricted almost entirely to the required site of action. The colistin concentration–time profile within the jejunum and ileum was established, and this enabled determination of the pharmacokinetic variables, maximum concentration ( C max) and area under curve (AUC) and derivation of the surrogate indices of antibacterial activity, C max/minimum inhibitory concentration (MIC) and AUC/MIC through integration of in vivo data with the results of in vitro potency studies for four strains of Escherichia coli. In the in vitro bacterial growth inhibition studies colistin acted by a concentration-dependent killing mechanism. Numerical values for the surrogate parameter AUC/MIC producing bactericidal and eradication effects of colistin against four strains of E. coli were established by PK–PD modeling based on the sigmoidal E max equation. These data were used to predict a daily dosage regimen for colistin.

Target-mediated drug disposition model: relationships with indirect response models and application to population PK–PD analysis

The paper focuses on approximations of the target-mediated drug disposition (TMDD) model as applied to pharmacodynamic (target kinetics) modeling. The TMDD equation for the total target concentration is shown to coincide with the indirect response model with stimulation or inhibition of elimination. This correspondence allows estimation of pharmacodynamic TMDD parameters and unobservable free target concentrations using indirect-response models. The ability of the TMDD model and its approximations to estimate the unobservable free target concentration is investigated by simulation. Pharmacokinetic parameters used for simulations were parameters typical for monoclonal antibodies. TMDD binding and target turnover parameters were similar to those estimated for omalizumab. Free drug and total target concentrations were measured. The simulated population PK-PD study demonstrated that for drugs with TMDD, indirect-response models are in fact mechanistic models that can be used to estimate TMDD model parameters and unobservable free target concentrations that are important for pharmacodynamic modeling.