Philip Chaikin

Pharmacokinetic/Pharmacodynamic Modeling in Drug Research and Development

The two domains in clinical pharmacology dealing with optimizing dosing recommendations are pharmacokinetics and pharmacodynamics. However, the usefulness of these disciplines is limited if viewed in isolation. Pharmacokinetic/pharmacodynamic (PK/PD) relationships and modeling builds the bridge between these two classical disciplines of clinical pharmacology. It links the concentration‐time profile as assessed by pharmacokinetics to the intensity of observed response as quantified by pharmacodynamics. Thus, the resulting so‐called integrated PK/PD‐models allow the description of the complete time course of the desired and/or undesired effects in response to a drug therapy. PK/PD‐modeling can elucidate the causative relationship between drug exposure and response and provide a better understanding of the sequence of events that result in the observed drug effect. This information can then be used to streamline the drug development process and dose optimization. This consensus paper presents an update on the current state of PK/PD‐modeling from an academic, industrial and regulatory perspective.

Defining the Maximum Tolerated Dose: Investigator, Academic, Industry and Regulatory Perspectives

The maximum tolerated dose (MTD) is an important concept in drug development, as it determines the optimal dose range for efficacy trials.14 Determination of the MTD in Phase I helps to ensure both that the doses tested in Phase II are safe and that the potentially efficacious dose range is evaluated. At present, there is no consensus regarding what constitutes an MTD in humans. Considerable confusion arises from the use of different operational definitions of the MTD and from the failure of many investigators to state their definitions of the MTD in reporting their studies. The MTD has been variously defined as the maximum dose administered during a trial that elicits no toxicity,5 the dose that produces mild to moderate sublethal toxic effects in a significant percent of individuals,6 or some percentile of the tolerance distribution.7 We believe that a discussion of the MTD will help clarify the important issues and promote standardization. A variety of perspectives are presented in this arti-

Pharmacokinetics/Pharmacodynamics in Drug Development: An Industrial Perspective

In a health care environment dominated by the growth of managed care organizations, generic competition, therapeutic substitution and drug utilization review, drug development is an extremely risky proposition. Consequently, it is imperative to incorporate a mechanistic approach to drug development that combines a thorough understanding of a drug at the molecular/cellular level with a rigorous preclinical, and clinical pharmacology program. This should enable the sponsor to evaluate multiple hypotheses during the early “learning” phases of clinical development (Phases I and IIA) and to eliminate nonpromising candidates early on while drug development costs are low. Clinical research done properly in the early stages of drug development will also set the stage for designing and conducting optimal “confirming” registrational Phase IIB/III studies for promising drug candidates. Pharmacokinetics (PK) and pharmacodynamics (PD) modeling and simulation are crucial components of a mechanistic approach to optimal drug development and their application has significant impact in both early and late development efforts. This communication describes several applications of pharmacokinetics and pharmacodynamics modeling and simulation that were important in guiding, optimizing and ensuring the success of development efforts for drug candidates in the therapeutic areas of cardiology and oncology. These examples are used to illustrate and discuss the use of the current state‐of‐the‐art in pharmacokinetics and pharmacodynamics modeling and simulation at numerous stages in the development cycle and to postulate on future directions in this area.

Absolute oral versus inhaled bioavailability: significance for inhaled drugs with special reference to inhaled glucocorticoids.

Orally inhaled drugs provide great benefit in the treatment of asthma as they are delivered directly to the site of action, i.e. the lung. The absolute oral inhaled bioavailability of a glucocorticoid results from the combination of the bioavailability of the dose delivered to the lung and the bioavailability of the dose delivered into the gastrointestinal (GI) tract. The majority of the dose delivered to the lung is absorbed and available systemically. For the portion of the glucocorticoid dose delivered orally, bioavailability depends upon absorption from the GI tract and the extent of first pass/pre‐systemic metabolism in the GI tissue and liver. Since this oral component of the delivered dose does not provide any beneficial therapeutic effect but can contribute to the systemic side effects, it is desirable for the absolute oral bioavailability of inhaled glucocorticoids to be relatively low (which is the case with most of the glucocorticoids, < 25%). Another approach to limiting systemic exposure from inhaled delivery is to improve the effectiveness of the oral inhaled formulation and delivery device, by increasing the fraction of the total inhaled dose which reaches the lung. Since current inhalation technology can provide respirable fractions in the range of 30–50%, what is the significance of the oral component of systemic exposure in relation to the overall systemic exposure following the oral inhalation administration of glucocorticoids? Below a certain point (<25%), lower oral bioavailability of inhaled drugs may not be clinically important with respect to systemic exposure if the lung targeting is good (30%).

Population pharmacokinetic analysis of istradefylline in healthy subjects and in patients with Parkinson's disease.

This model‐based analysis quantifies the population pharmacokinetics (PK) of orally administered istradefylline, a selective adenosine A2A receptor antagonist, in healthy subjects and patients with Parkinsons disease, including the estimation of covariate effects on istradefylline PK parameters. Istradefylline plasma concentration data from 8 phase 1 and 8 phase 2/3 studies conducted in 1449 patients and normal, healthy volunteers aged from 18 to 87 years were best described by a 2‐compartment model with first‐order absorption parameterized in terms of apparent oral clearance (CL/F), apparent central volume of distribution (V2/F), apparent intercompartmental clearance (Q/F), apparent peripheral volume of distribution (V3/F) and a first‐order absorption rate‐constant (Ka). The typical population PK parameters were CL/F (5.76 L/h), V2/F (198 L), Q (21.6 L/h), V3/F (307 L), and Ka (0.464 h−1) for a 70‐kg, nonsmoking Caucasian who had 55.6 kg of lean body mass, no presence of CYP3A4 inhibitors, and unknown food status. Smoking and CYP3A4 inhibitors as concomitant medications were important predictors of istradefylline exposure. Istradefylline area under the concentration‐time curve at steady‐state increased 35% (95% confidence interval, 18%‐55%) in the presence of CYP3A4 inhibitors and decreased 38% (95% confidence interval, 26%‐50%) in smokers. The population PK model described the observed concentration data well and was deemed appropriate for further evaluation of the istradefylline exposure‐response relationship in patients with Parkinsons disease.

Pharmacokinetics of Tinidazole in Male and Female Subjects

Abstract: Tinidazole is a potent nitroimidazole compound active against, and used to treat, Trichomonas vaginalis infections in males and females. Speculation exists in the literature that observed differences in tinidazole plasma concentrations between males and females may be due to sex‐mediated pharmacokinetic differences. To investigate this phenomenon, a study was designed to determine the pharmacokinetics of tinidazole in male and female subjects. Six male and six female volunteers were each administered a single 2‐Gm oral dose of tinidazole. Plasma and urine samples, collected over a 72‐hour period, were assayed by a sensitive and specific HPLC assay. Results demonstrate a significant correlation between tinidazole oral plasma clearance and body weight and apparent volume of distribution of tinidazole and body weight for male and female subjects, respectively. There were no apparent sex‐mediated differences in weight‐normalized pharmacokinetic parameters as documented by statistically equivalent mean oral plasma clearances (36.1 and 35.4 ml/kg/hour), apparent volumes of distribution (0.65 and 0.63 liter/kg), and elimination half‐lives (12.3 and 12.3 hours, males and females, respectively). Mean area under the tinidazole plasma concentration‐versus‐time curve and mean peak plasma concentration of tinidazole were 1.3 times greater for females than for males, apparently due to the smaller mean body weight of females and consequently a 1.3 times greater administered dose to the females on a weight basis.

Population Pharmacokinetic‐Pharmacodynamic Analysis of Istradefylline in Patients With Parkinson Disease

This model‐based analysis quantifies the population pharmacokinetic‐pharmacodynamic efficacy and safety/tolerability relationships of orally administered istradefylline, a selective adenosine A2A receptor antagonist, in healthy participants and patients with Parkinson disease. Data from 6 phase 2/3 clinical trials comprised the population database, with 1760 and 1798 patients contributing to the efficacy and safety/tolerability analyses, respectively. The relationship between istradefylline area under the curve at steady state and percentage OFF time was described by a nonlinear model (Emax) based on time for the disease progression/placebo response component and an Emax model for the effect of istradefylline. The typical maximum decrease in percentage OFF time due to istradefylline exposure would be 5.79% (95% confidence interval = 4.09%–7.49%) with one‐half of the maximum effect reached at an exposure of 1690 ng × hr/mL (95% confidence interval = 199–3180 ng × hr/mL). The pharmacokinetic‐pharmacodynamic relationships for dyskinesia and dizziness were described by an Emax model, and for nausea, a power model was used. The probabilities of dyskinesia and dizziness are expected to plateau at a dose of 40 mg/d, and the probability of nausea is expected to continually rise as the dose is increased. Collectively, these results support a starting istradefylline dose of 20 to 40 mg/d.

In vitro and in vivo techniques used in drug development for evaluation of dose delivery of inhaled corticosteroids.

Oral inhaled corticosteroids are important in the treatment of asthma since their delivery is targeted directly to the lung, which is the site of action. Triamcinolone acetonide (TAA) is an effective and safe corticosteroid that is marketed as a metered‐dose inhaler (MDI) with an integrated spacer (Azmacort®) for the treatment of asthma. Due to the phasing out of chlorofluorocarbon (CFC) propellants, Azmacort® has been reformulated with a non‐CFC propellant. Due to the complexities of oral inhaled formulations and the topical nature of drug delivery to the lung for efficacy, the reformulation of oral inhaled MDIs requires careful consideration and support throughout their development, using a combination of in vitro and in vivo studies to ensure clinical comparability for both efficacy and safety. This paper describes a chronological series of studies designed to support the reformulation of Azmacort®. These included in vitro studies to estimate respirable fraction, in vivo pulmonary deposition studies, in vivo pharmacokinetic‐pharmacodynamic studies to estimate the systemic effects of each formulation, and final clinical studies in adult and pediatric patients to confirm the clinical comparability of the new formulation of Azmacort®. The results of these studies, performed at various stages during the development of new formulations, were critical in guiding the reformulation efforts for Azmacort®.

The Bial 10‐2474 Phase 1 Study—A Drug Development Perspective and Recommendations for Future First‐in‐Human Trials

BIA 10‐2474 (a fatty acid amide hydrolase inhibitor) was evaluated in a first‐in‐human phase 1 study in normal volunteers to assess safety/tolerability, pharmacokinetics, pharmacodynamics, and food effect. The dose‐escalation process consisted of a single‐ascending‐dose phase (SAD) and multiple‐ascending‐dose phase (MAD). Prospective determination of the starting dose and maximal escalated dose was consistent with the usual clinical pharmacology principles for extrapolation of preclinical toxicology data to human equivalent doses. After only 5–6 days of multiple‐dose administration of 50 mg daily in the MAD phase, several subjects became quite ill with central nervous system symptoms. One subject progressed to brain death within several days of symptom onset. Magnetic resonance imaging scans demonstrated signal abnormalities consistent with microbleeds affecting the hippocampus and pons, suggestive of possible cytotoxic or vasogenic edema compatible with a toxic/metabolic process. There were no findings at lower MAD doses or during the SAD phase. The toxicology program carried out in 4 preclinical species (mouse, rat, dog, and monkey) did not demonstrate significant neurotoxicity. The probable mechanism of neurologic toxicity demonstrated in humans at the 50‐mg daily dose was inhibition of off‐target cerebral receptors or through another mechanism. Additional recommendations have been proposed for future first‐in‐human studies to maximize subject safety. However, one must also accept the basic premise that, in general, first‐in‐human phase 1 studies are remarkably safe, and these rare events are not 100% avoidable during the drug development process.

Industry Perspectives on the MTD: Growing Acceptance in Clinical Development Programs

T concept of defining a dose in Phase I clinical pharmacology studies that elicits unacceptable adverse effects in subjects (patients) is an important first step in the understanding and refinement of the appropriate dose range to be evaluated in Phase II studies. Phase I singleand repeat-dose tolerance studies provide the unique opportunity to define the acute dose-limiting toxicity of a drug and to examine the potential concentration-toxicity relationship, as well as to gather as much information as possible regarding the concentration-effect relationship, incorporatingbiologic/ surrogate markers. Overly conservative dosing strategies in first-in-man studies can result in lengthy and expensive Phase I trials and result in subtherapeutic doses in Phase II that can contribute to delays and failures in drug development. Defining the MTD at an early stage of development increases the likelihood of success in Phase II efficacy trials by extending the upper limit of the dose range to be tested. This may eliminate the need to repeat Phase II trials with a higher dose in case of failure to demonstrate efficacy. An understanding of the acute doselimiting toxicity from Phase I studies will help to clarify the therapeutic index of a drug and establish a correlation with systemic exposures that may occur in populations at risk (i.e., renal and hepatic impairment). Therefore, it is important to identify doses defined as the MID and the MTD, and there is an increased recognition of these concepts in industry. The concept of MTD is well recognized in oncology for cytotoxic drugs, yet variability exists regarding definition of dose-limiting toxicity (DLT) and definitions of the MTD and recommended dose for Phase II. The MTD concept is even less well standardized in other therapeutic areas. The assessment of MTD or highest dose tested in Phase I studies can be based on a combination/hierarchy of the following parameters: (1) dose-limiting toxicity (clinical signs/symptoms/laboratory parameters) that can define the true MTD, (2) pharmacodynamic markers, and (3) pharmacokinetic parameters (considering the achievement of targeted plasma concentrations in man associated with pharmacologic activity in relevant preclinical animal models). As Dr. Cutler has previously mentioned, we need to identify a dose in Phase I that demonstrates appropriate dose-limiting toxicity (DLT) in a sufficient number of subjects or patients to define the upper boundary of dose escalation. The determination of DLT should be based on indication-specific prospective criteria and is sponsor and investigator dependent. Establishing the maximum end point for dose-limiting toxicity can be very subjective and depends on the qualitative nature of the drug toxicity. Dr. Cutler has referred to the MID as the dose at which one observes DLT in ≥ 50% of subjects; the MTD is usually the dose immediately below that and is the top dose recommended for Phase II trials. However, by convention, it is rare to see the term MID used in oncology studies; the term more universally applied is the MTD, which is the top dose based on dose-limiting toxicity. Reports from the oncology literature define the MTD as the dose at which between one-third and two-thirds of the patients in a dose cohort demonstrate DLT. The dose immediately below this is usually the recommended dose for Phase II. Thus, although the terminology is different, the concepts are the same as for nononcology trials. However, it is easy to recognize why these terms generate confusion, especially across therapeutic areas. Furthermore, there is lack of standardization of terminology even within the same therapeutic area. For example, within the oncology literature, on occasion the term MTD will be synonymous with the recommended dose for Phase II trials. A recent study reviewed 40 Phase I oncology trials for cytotoxic drugs. In 75% (30/40) of the trials, the dose level immediately below the MTD was taken as the top dose going forward