Ryosei Kawai

Physiologically based pharmacokinetic study on a cyclosporin derivative, SDZ IMM 125.

The immunosuppressant, SDZ IMM 125 (IMM), is a derivative of cyclosporin A (CyA). The disposition kinetics of IMM in plasma, blood cells, and various tissues of the rat was characterized by a physiologically based pharmacokinetic (PBPK) model; the model was then applied to predict the disposition kinetics in dog and human. Accumulation of IMM in blood cell is high (equilibrium blood cell/plasma ratio=8), although the kinetics of drug transference between plasma and blood cell is moderately slow, taking approximately 10 min to reach equilibrium, implying a membranelimited distribution into blood cells. A local PBPK model, assuming blood-flow limited distribution and tissue/blood partition coefficient (KP) data, failed to adequately describe the observed kinetics of distribution, which were slower than predicted. A membrane transport limitation is therefore needed to model dynamic tissue distribution data. Moreover, a slowly interacting intracellular pool was also necessary to adequately describe the kinetics of distribution in some organs. Three elimination pathways (metabolism, biliary secretion, and glomerular filtration) of IMM were assessed at steady statein vivo and characterized independently by the corresponding clearance terms. A whole-body PBPK model was developed according to these findings, which described closely the IMM concentration-time profiles in arterial blood as well as 14 organs/tissues of the rat after intravenous administration. The model was then scaled up to larger mammals by modifying physiological parameters, tissue distribution and elimination clearances;in vivo enzymatic activity was considered in the scale-up of metabolic clearance. The simulations agreed well with the experimental measurements in dog and human, despite the large interspecies difference in the metabolic clearance, which does not follow the usual allometric relationship. In addition, the nonlinear increase in maximum blood concentration andAUC with increasing dose, observed in healthy volunteers after intravenous administration, was accommodated quantitatively by incorporating the known saturation of specific binding of IMM to blood cells. Overall, the PBPK model provides a promising tool to quantitatively link preclinical and clinical data.

Physiologically based pharmacokinetic modeling as a tool for drug development

Since the pioneering work of Haggard and Teorell in the first half of the 20th century, and of Bischoff and Dedrick in the late 1960s, physiologically based pharmacokinetic (PBPK) modeling has gone through cycles of general acceptance, and of healthy skepticism. Recently, however, the trend in the pharmaceuticals industry has been away from PBPK models. This is understandable when one considers the time and effort necessary to develop, test, and implement a typical PBPK model, and the fact that in the present-day environment for drug development, efficacy and safety must be demonstrated and drugs brought to market more rapidly. Although there are many modeling tools available to the pharmacokineticist today, many of which are preferable to PBPK modeling in most circumstances, there are several situations in which PBPK modeling provides distinct benefits that outweigh the drawbacks of increased time and effort for implementation. In this Commentary, we draw on our experience with this modeling technique in an industry setting to provide guidelines on when PBPK modeling techniques could be applied in an industrial setting to satisfy the needs of regulatory customers. We hope these guidelines will assist researchers in deciding when to apply PBPK modeling techniques. It is our contention that PBPK modeling should be viewed as one of many modeling tools for drug development.

Physiologically Based Pharmacokinetics of Cyclosporine A: Reevaluation of Dose–Nonlinear Kinetics in Rats

The disposition kinetics of Cyclosporine A (CyA) in rat, based on measurement in arterial blood, appeared dose-linear over a wide iv dose range (1.2–30mg/kg). Physiologically based pharmacokinetic (PBPK) analysis, however, demonstrated that this was an apparent observation resulting from counterbalancing nonlinear factors, such as saturable blood and tissue distribution, as well as clearance (CLb). A PBPK model was successfully developed taking into account these multiple nonlinear factors. Tissue distribution was distinctly different among various organs, being best described by either a linear model (muscle, fat; Model 1), one involving instantaneous saturation (lung, heart, bone, skin, thymus; Model 2), noninstantaneous saturation (kidney, spleen, liver, gut; Model 3), or one with saturable efflux (brain; Model 4). Overall, the whole body volume of distribution at steady state for unbound CyA (Vuss) decreased with increasing dose, due at least in part to saturation of tissue-cellular cyclophilin binding. Clearance, essentially hepatic, and described by the well-stirred model, was also adequately characterized by Michaelis–Menten kinetics, Km0.60 μg/ml. In model-based simulations, both volume of distribution at steady state (Vss,b) and CLbvaried in a similar manner with dose, such that terminal t1/2remained apparently unchanged; these dose responses were attenuated by saturable blood binding. CyA concentration measured in arterial blood was not always directly proportional to the true exposure, i.e., unbound or target tissue concentrations. The PBPK model not only described comprehensively such complicated PK relationships but also permitted assessment of the sensitivity of individual parameters to variation in local nonlinear kinetics. Using this approach, dose-dependent CyA uptake into brain was shown to be sensitive to both active and passive transport processes, and not merely the affinity of the active (efflux) transporter at the level of the blood–brain barrier.

Nonparametric analysis of the absorption profile of octreotide in rabbits from long-acting release formulation OncoLAR

Octreotide (octreotide-acetate, Sandostatin(R)) is a somatostatin analogue, used in long-term treatment of acromegaly. The present study describes the absorption profile in rabbits of octreotide after release from the long-acting formulation OncoLAR (denoted as octreotide-LAR). In a first experiment, the disposition kinetics of octreotide was studied for 24 h in six rabbits after intravenous (i. v.) injection of 0.025 mg of a solution of octreotide. In a second experiment, release kinetics was studied in eight rabbits for 49 days after an i.m. injection of 5 mg/kg of octreotide-LAR. Concentrations were determined by radioimmunoassay. After i.v. injection of octreotide, one- and two-compartment models were compared for each rabbit. A typical disposition profile was computed using the mean parameters. After i.m. injection of octreotide-LAR, deconvolution was performed using the point-area method. Individual absorption profiles were characterised using natural splines. The number of breakpoints was selected using the generalised cross-validation criterion. The two compartment model was selected based on the i.v. study. After i.m. administration, octreotide exhibited a triphasic absorption profile, with large interindividual variability. A transient peak followed the initial burst phase. The third phase covered 85% of total drug released. The approach allows a model-independent description of the in vivo absorption profile of octreotide-LAR.

Population pharmacodynamic analysis of octreotide in acromegalic patients

Octreotide is an octapeptide analog of somatostatin used to normalize growth hormone levels in acromegaly. This article presents a population analysis of the relationship between octreotide and growth hormone concentrations in 94 patients with acromegaly, including 10 patients responding incompletely to subcutaneous treatment (poor responders).

Modeling the kinetics of release of octreotide from long‐acting formulations injected intramuscularly in rabbits

Long-acting repeatable formulations (LAR) based on polymeric microspheres were manufactured to deliver octreotide, an octapeptide analogue used in acromegaly. We developed a model to describe the complex triphasic concentration versus time profile observed in rabbits after intramuscular (i.m.) injection of these LAR formulations. A 5-mg x kg(-1) dose of octreotide in a reference LAR formulation was given im to eight rabbits; two groups of four rabbits each received a different formulation. In each animal, 26 blood samples were taken over 49 days. Concentrations of octreotide were assayed by radioimmunoassay. A model describing the concentration profile was developed. Octreotide release was described using the succession of an exponential model, a semiempirical non-Fickian model, and a delayed Weibull model. Parameters were estimated using nonlinear regression, first for the eight rabbits that received the reference formulation and then for the other eight animals. The model provides an adequate description of the concentration versus time profile for the three formulations. For the reference phase, erosion accounted for 87% of total drug release. The formulation encapsulating an octreotide-acetate complex showed a prolonged diffusion phase.

PHARMACOKINETIC CONSIDERATION ON THE PULMONARY ABSORPTION OF INHALED CYCLOSPORINE

Disposition of micronized cyclosporine A (CyA) dry powder in rats administered by inhalation route was characterized by physiologically-based pharmacokinetic (PBPK) model. At the end of one hour inhalation (10 mg/kg), 30 % of dose was deposited in the lung, while the rest (70 %) was recovered in digestive organs (mouth, stomach, and intestine). PBPK model analyses on the blood and tissue measurements post-inhalation suggested only 5 % of dose was absorbed via pulmonary route; the rest in the lung (25%) was considered slowly (t1/2>20h) transfer to mouth and swallowed into digestive route. These kinetic information help assessing efficacy (when applied to bronchial asthma) and toxicity (systemic exposure) in a dynamic fashion.

PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING OF CYCLOSPORINE DERIVATIVES IV

A pharmacokinetic analytical method is presented, which was developed in Sandoz during the preclinical evaluation of a cyclosporine derivative, SDZ IMM 125. A physiologically-based pharmacokinetic (PBPK) model established based on rat data was scaled-up to those for dog and human using 1) an allometric equation for estimating transmembrane drug exchange clearance for each organ in the larger mammals, and 2) relative activity ratios of a specific cyt.P-450 subtype among rat, dog, and human, which were measured in vitro. The resultant PBPK models for dog and human successfully predicted the blood kinetics of SDZ IMM 125 measured experimentally during preclinical and clinical pharmacokinetic studies. The technique seems to facilitate the safety assessment in humans at very early period of drug development.