An overview is provided of the present population analysis methods and an assessment of which software packages are most appropriate for various PK/PD modeling problems. Four PK/PD example problems were solved using the programs NONMEM VI beta version, PDx-MCPEM, S-ADAPT, MONOLIX, and WinBUGS, informally assessed for reasonable accuracy and stability in analyzing these problems. Also, for each program we describe their general interface, ease of use, and abilities. We conclude with discussing which algorithms and software are most suitable for which types of PK/ PD problems. NONMEM FO method is accurate and fast with 2-compartment models, if intra-individual and interindividual variances are small. The NONMEM FOCE method is slower than FO, but gives accurate population values regardless of size of intra-and interindividual errors. However, if data are very sparse, the NONMEM FOCE method can lead to inaccurate values, while the Laplace method can provide more accurate results. The exact EM methods (performed using S-ADAPT, PDx-MCPEM, and MONOLIX) have greater stability in analyzing complex PK/PD models, and can provide accurate results with sparse or rich data. MCPEM methods perform more slowly than NONMEM FOCE for simple models, but perform more quickly and stably than NONMEM FOCE for complex models. WinBUGS provides accurate assessments of the population parameters, standard errors and 95% confi dence intervals for all examples. Like the MCPEM methods, WinBUGS's effi ciency increases relative to NONMEM when solving the complex PK/PD models.

No abstract

AimsSD‐1077, a selectively deuterated precursor of dopamine (DA) structurally related to L‐3,4‐dihydroxyphenylalanine (L‐DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD‐1077.MethodsPlasma and urine PK of drug and metabolites and safety after a single oral 150 mg SD‐1077 dose were compared to 150 mg L‐DOPA, each in combination with 37.5 mg carbidopa (CD) in a double‐blind, two‐period, crossover study in healthy volunteers (n = 16).ResultsGeometric least squares mean ratios (GMRs) and 90% confidence intervals (90% CI) of SD‐1077 vs. L‐DOPA for Cmax, AUC0–t, and AUC0–inf were 88.4 (75.9–103.1), 89.5 (84.1–95.3), and 89.6 (84.2–95.4), respectively. Systemic exposure to DA was significantly higher after SD‐1077/CD compared to that after L‐DOPA/CD, with GMRs (90% CI) of 1.8 (1.45–2.24; P = 0.0005) and 2.06 (1.68–2.52; P < 0.0001) for Cmax and AUC0–t and a concomitant reduction in the ratio of 3,4‐dihydroxyphenylacetic acid/DA confirming slower metabolic breakdown of DA by monoamine oxidase (MAO). There were increases in systemic exposures to metabolites of catechol O‐methyltransferase (COMT) reaction, 3‐methoxytyramine (3‐MT) and 3‐O‐methyldopa (3‐OMD) with GMRs (90% CI) for SD‐1077/CD to L‐DOPA/CD for 3‐MT exposure of 1.33 (1.14–1.56; P = 0.0077) and 1.66 (1.42–1.93; P < 0.0001) for Cmax and AUC0–t, respectively and GMRs (90% CI) for 3‐OMD of 1.19 (1.15, 1.23; P < 0.0001) and 1.31 (1.27, 1.36; P < 0.0001) for Cmax and AUC0–t. SD‐1077/CD exhibited comparable tolerability and safety to L‐DOPA/CD.ConclusionsSD‐1077/CD demonstrated the potential to prolong exposure to central DA at comparable peripheral PK and safety to the reference L‐DOPA/CD combination. A single dose of SD‐1077 is safe for further clinical development in Parkinson's disease patients.

No abstract

A distributed delay approach was proposed in this paper to model delayed outcomes in pharmacokinetics and pharmacodynamics studies. This approach was shown to be general enough to incorporate a wide array of pharmacokinetic and pharmacodynamic models as special cases including transit compartment models, effect compartment models, typical absorption models (either zero-order or first-order absorption), and a number of atypical (or irregular) absorption models (e.g., parallel first-order, mixed first-order and zero-order, inverse Gaussian, and Weibull absorption models). Real-life examples were given to demonstrate how to implement distributed delays in Phoenix NLME™ 8.0, and to numerically show the advantages of the distributed delay approach over the traditional methods.

The clinical phase of drug development should be concluded sooner and at a lower cost if primarily only the pivotal and supportive studies were to be conducted. Such improved efficiency requires development of a decision support system that delivers five new capabilities: (i) it enables one to predict a result of a clinical study and to identify those studies that are expected to have an acceptable probability of success; (ii) it will allow one to optimally utilize available pharmacokinetic and pharmacodynamic (PK/PD) data and improve its predictive capability as more data become available; (iii) it will enable one to project useful population results, not just mean results; (iv) predictions will be accompanied by a measure of reliability; and (v) expected initial clinical results will be predictable from animal and related drug class data. With such a tool population targets could be specified very early in the drug development programme, challenged, and then rationally revised at each step during the development process. This report describes progress in developing and testing a clinical trials Forecaster, a prototype for such a system. The Forecaster generates estimates of the joint density for a population of combined PK/PD parameters. That population then serves as a surrogate for the population of individuals. When the resulting joint density is sampled, the obtained sets of parameters may be used to generate data that is statistically indistinguishable from the original experimental data. Such simulated data can be used to validate assumptions, and make inferences on specified population targets that are accompanied by a measure of prediction reliability. We demonstrate use of the forecaster by employing N = 22 PK/PD parameter sets for an orally administered analgesic.

The CD40 antigen is expressed in most B-cell malignancies, including chronic lymphocytic leukemia (CLL), and represents an attractive target for antibody therapy. HCD122 is a high affinity, fully human IgG1 antagonistic anti-CD40 monoclonal antibody designed to exert antitumor activity as an inhibitor of CD40-ligand-mediated survival signals and as a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). In this phase 1 study to determine maximum tolerated dose (MTD) in CLL, eligible patients (pts) include those with relapsed or refractory disease after prior fludarabine treatment and are assigned to receive one cycle of 4 weekly infusions of HCD122 at doses ranging from 0.3 to 10 mg/kg depending upon the dose cohort. A standard phase I design is used with each dose cohort enrolling 3–6 pts for evaluation of MTD, toxicity, pharmacokinetics (PK), and pharmacodynamics (PD). To date, 14 pts have been treated at 3 dose levels: 3 pts at 0.3 mg/kg, 4 pts at 1 mg/kg, and 7 pts at 3 mg/kg. Median patient age was 65 yrs (41–74 yrs); median number of prior therapies was 3 (2–11); median WBC at enrollment was 38.8 K/μ L (3.4–284 K/μ L). No dose limiting toxicity (DLT) occurred at the 0.3 and 1 mg/kg dose levels. At 3 mg/kg, streptococcal sepsis was reported in 1 pt after 2 study infusions and was considered DLT. Transient asymptomatic grade 3 or 4 elevation of amylase and/or lipase occurred in 2 subjects. In 9 pts with available data, infusions were associated with manageable grade 1–2 toxicity, primarily chills (7 pts), nausea (4 pts), and fever (3 pts) that was most predominant with the first infusion. PK analysis showed rapid clearance of HCD122 at the 0.3 and 1mg/kg dose levels, with no detectable levels at 2 and 7 days after infusion, respectively. PK data were available from 6 of 7 patients receiving 3mg/kg. These data indicated that some accumulation of HCD122 occurred at this dose level. Complete antigen saturation data were available for 2 of these subjects. Both showed sustained 100% saturation of antigen on peripheral CD5+CD19+ cells throughout the treatment period. Peripheral CD40+ CLL cells dropped transiently with a mean of 31% during each infusion in the majority of patients but the decreases were not maintained week-to-week. There were no substantive changes in NK or T-cell populations during therapy. In summary, HCD122 was safe and well tolerated up to the 3mg/kg dose level that is currently under evaluation. PK analysis to date suggests that levels higher than 3 mg/kg will be necessary to sustain levels of HCD122 in the expected therapeutic range, and dose escalation will continue to the maximum tolerated dose.

HCD122 is a novel, fully human, IgG1 antagonistic monoclonal antibody targeting the CD40 receptor. This antibody blocks CD40-mediated signaling and is a potent mediator of antibody-dependent cellular cytotoxicity (ADCC). Previous preclinical investigation confirmed expression of CD40 on myeloma cells in the majority of patients and reported antitumor activity of HCD122 against multiple myeloma cells ex vivo (Tai, Y et al. Cancer Res2005; 65(13): 5898–5906). This ongoing phase 1 study will determine the maximum tolerated dose of CHIR-12.12 in multiple myeloma patients (pts) who are relapsed or refractory after at least one prior therapy. Planned dose levels are 1, 3 and 10 mg/kg administered IV once weekly for 4 weeks. Each dose group will enroll 3–6 pts to evaluate safety, pharmacokinetics (PK) and clinical response. To date, 9 pts have been treated at 2 dose levels: 3 pts at 1 mg/kg and 6 pts at 3 mg/kg. Median patient age is 65 yrs (46–81 yrs); median number of prior therapies is 3 (2–12). No dose limiting toxicity (DLT) occurred at the 1mg/kg dose level. At 3 mg/kg, 1 DLT of grade 4 thrombocytopenia occurred in 1 pt. No other grade 3 and 4 lab abnormalities and adverse events have been reported. In 7 pts with available data, infusions were well tolerated, with easily managed grade 1–2 toxicities, primarily chills (5 pts), nausea (3 pts), pyrexia (2 pts), and arthralgia (2 pts) mainly reported during the first infusion. Preliminary PK analysis showed more than dose proportional - increase in Cmax and AUC at the 3 mg/kg dose level compared to the 1 mg/kg dose level. At the 3 mg/kg dose, antibody accumulation occurred week-to-week; the mean Cmax after the fourth infusion on Day 22 was 126.1 mg/mL(range 52 – 195 ug/mL) and HCD122 levels were measurable up to Day 57 and in one patient up to Day 99. One week after the last 3 mg/kg dose, trough levels ranged from 28 to 109 mg/mL. Of the 3 pts at 1 mg/kg, one showed stable disease (SD) for >23 weeks and two had progressive disease (PD) by week 5. Of the 6 pts at 3 mg/kg, one had partial response (PR) at week 9 and was confirmed at week 15, one had SD for > 5 weeks, and 4 had PD at week 5. One pt with PD terminated the study before final safety evaluation, and must be replaced before assessment of the 3mg/kg dose level is complete. Thus, in preliminary studies, HCD122 appears to be safe and well tolerated to date at doses of 1 mg/kg and 3 mg/kg weekly for 4 doses and shows promising anti-myeloma activity. Enrollment is continuing to determine MTD.