Diane R. Mould

Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms.

Crohns disease and ulcerative colitis are chronic inflammatory disorders resulting from immune dysregulation. Patients who fail conventional medical therapy require biological treatment with monoclonal antibodies (mAbs). Although mAbs are highly effective for induction and maintenance of clinical remission, not all patients respond, and a high proportion of patients lose response over time. One factor associated with loss of response is immunogenicity, whereby the production of antidrug antibodies accelerates mAb clearance. However, other factors related to patient and disease characteristics also influence the pharmacokinetics of mAbs. These factors include gender, body size, concomitant use of immunosuppressive agents, disease type, serum albumin concentration, and the degree of systemic inflammation. Because it is important to maintain clinically effective concentrations to provide optimal clinical response and drug exposure is affected by patient factors, a better understanding of the pharmacology of mAbs will ultimately result in better patient care.

Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development.

Monoclonal antibodies (mAbs) have complex pharmacology; pharmacokinetics and pharmacodynamics depend on mAb structure and target antigen. mAbs targeting soluble antigens often exhibit linear phar-macokinetic behavior, whereas mAbs targeting cell surface antigens frequently exhibit nonlinear behavior due to receptor-mediated clearance. Where nonlinear kinetics exist, clearance can change due to receptor loss following repeated dosing and/or disease severity. mAb pharmacodynamics are often indirect, with delayed clinically relevant outcomes. This behavior provides challenges during clinical development; studies must be carefully planned to account for complexities specific to each agent.Selection of a starting dose for human studies can be difficult. Species differences in pharmacology need to be considered. Various metrics are available for scaling from animals to humans. Optimal dose selection should ensure uniform mAb exposure across all individuals. Traditional approaches such as flat dosing and variable dosing based upon body surface area or weight should be supported by pharmacokinetic and pharmacodynamic behavior, including target antigen and concurrent disease states. The use of loading doses or dose adjustments to improve clinical response is also a consideration.The evaluation of drug interactions requires innovative designs. Due to the pharmacokinetic properties of mAbs, interacting drugs may need to be administered for protracted periods. Consequently, population pharmacokinetic and pharmacodynamic model-based approaches are often implemented to evaluate mAb drug interactions.

A phase I trial of humanized anti-interleukin 2 receptor antibody in renal transplantation.

The efficacy of murine monoclonal anti-interleukin 2 alpha chain receptor (Tac) antibodies is limited by a short half-life and the development of antibodies to the heterologous protein. The safety, pharmacokinetics-dynamics, and immunosuppressive effect of a humanized anti-Tac antibody (HAT) was evaluated in 12 renal transplant recipients. Ten patients received living related transplants (three HLA-identical matches and seven one-haplotype or zero-haplotype matches) and two patients received cadaver organs. The patients were divided into four HAT treatment arms: 0.5 mg/kg/week (n=4), 1 mg/kg/week (n=2), 0.5 mg/kg every other week (n=3), and 1 mg/kg every other week (n=3). The first dose of HAT was given within 12 hr before transplantation, and four additional doses were given after transplantation. Patients were also placed on cyclosporine, steroids, and azathioprine. Only one patient, a recipient of a cadaver kidney in the lowest HAT treatment arm, had a reversible rejection episode. The 10 recipients of living related transplants were compared with 17 historical controls treated with an identical immunosuppressive regimen except for HAT. Whereas none of the HAT-treated living related donor recipients had a rejection episode, 6 of 17 (41%) of the historical controls had a rejection episode in the first year after transplantation. There were no first-dose reactions after HAT therapy or other subsequent side effects. None of the patients experienced opportunistic infections or malignancies. One patient developed low-titer anti-HAT antibodies, although the patient maintained high serum HAT concentrations throughout the study. Immune monitoring showed that there were no changes in the percentage or absolute counts of CD3 cells or T-cell subsets after HAT therapy. However, there was a significant decrease in the number of circulating lymphocytes that expressed free Tac. The overall harmonic mean half-life of HAT was 273 hr. The results of this study indicate that HAT given at 1 mg/kg every other week for a total of five doses may provide therapeutic HAT concentration levels and result in good saturation of Tac receptors for at least 12 weeks after transplantation. In summary, HAT is safe and is well tolerated by patients. Its long half-life and lack of immunization could make it a very useful immunosuppressive drug.

Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa‐2a and a polyethylene glycol‐modified derivative in healthy subjects

Interferon alfa‐2a was chemically modified by the covalent attachment of a polyethylene glycol (PEG) moiety to enhance its circulating half‐life and to reduce its immunogenicity. A comparative evaluation of the pharmacokinetics of the PEG‐modified interferon alfa‐2a showed a greater than twofold increase in the circulating half‐life as a result of this chemical modification. An indirect physiologic response model was developed to characterize the time course of the MX protein response after subcutaneous administration of single ascending doses of either interferon alfa‐2a or PEG‐interferon alfa‐2a in healthy volunteers. Analysis of the pharmacokinetic‐pharmacodynamic relationship suggested that the PEG‐modified interferon alfa‐2a could not be administered less than twice weekly and therefore offered little therapeutic advantage over its unmodified counterpart, which is administered three times weekly. These results were consistent with findings in phase II trials. This study substantiates the usefulness of pharmacodynamic modeling as a tool for the development of dose recommendations and for the early selection of drug candidates in the drug development process.

A population pharmacokinetic-pharmacodynamic analysis of single doses of clenoliximab in patients with rheumatoid arthritis

Clenoliximab (IDEC‐151) is a macaque‐human chimeric monoclonal antibody (immunoglobulin G4) specific for the CD4 molecule on the surface of T lymphocytes. It is being studied in patients with rheumatoid arthritis in which T cell activation orchestrates inflammation and tissue damage. In this initial study in humans, the pharmacokinetics and pharmacodynamics of clenoliximab were investigated after single intravenous infusion. Blood was collected up to 12 weeks after dose administration to measure clenoliximab concentration, CD4+ T‐cell count, CD4 antigen coating, and CD4 cell surface density. Clenoliximab displayed nonlinear pharmacokinetic behavior and caused an 80% reduction in CD4 density for up to 3 weeks, without depleting T cells. A pharmacokinetic‐pharmacodynamic model was developed that described the relationship between antibody concentration, antigen coating, and the observed decreases in CD4 cell surface density. This was used to anticipate the effects of clenoliximab in untested regimens and optimize the design of future clinical trials.

Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors

Our objective was to describe the pharmacokinetics and pharmacodynamics of topotecan in patients.

Simultaneous modeling of the pharmacokinetics and pharmacodynamics of midazolam and diazepam.

The pharmacokinetics and pharmacodynamics of midazolam and diazepam were compared after intravenous infusions of 0.03 and 0.07 mg/kg midazolam and 0.1 and 0.2 mg/kg diazepam on four separate occasions in 12 healthy male subjects in a randomized four‐way crossover design. The Digit Symbol Substitution Test (DSST) was used as a measure of drug effect. Subjects performed three practice tests before dosing to account for any effects caused by familiarization (“learning curve”) with the testing procedure. Pharmacokinetic and pharmacodynamic data were simultaneously fitted to a semiparametric model. In this model, a pharmacokinetic model related dose to plasma concentrations, a link model related plasma concentrations to the concentration at the effect site, and a pharmacodynamic model related the effect site concentration to the observed effect. The plasma—effect site equilibrium half‐life was approximately 2½ times longer for midazolam than for diazepam, which is in good agreement with previously published data. Based on the estimated effect site concentration at which half of the maximal effect was reached, midazolam had approximately a sixfold greater intrinsic potency than diazepam. This difference in potency was also observed in a previous study that used transformed electroencephalographic (EEG) data to assess pharmacodynamic activity. The findings reported here with a clinically relevant pharmacodynamic marker (DSST) confirm the utility of surrogate drug effect measures such as EEG. This work also shows the feasibility of conducting pharmacokinetic pharmacodynamic analysis during the drug development process.

Pharmacokinetics of Sapropterin in Patients with Phenylketonuria

AbstractBackground and objective: Untreated phenylketonuria is characterized by neurocognitive and neuromotor impairment, which result from elevated blood phenylalanine concentrations. To date, the recommended management of phenylketonuria has been the use of a protein-restricted diet and the inclusion of phenylalanine-free protein supplements; however, this approach is often associated with poor compliance and a suboptimal clinical outcome. Sapropterin dihydrochloride, herein referred to as sapropterin, a synthetic formulation of 6R-tetrahydrobiopterin (6R-BH4), has been shown to be effective in reducing blood phenylalanine concentrations in patients with phenylketonuria. The objective of the current study was to characterize the pharmacokinetics and pharmacokinetic variability of sapropterin and to identify the characteristics that influence this variability. Patients and methods: This was a 12-week, fixed-dose phase of an open-label extension study. The study was conducted at 26 centres in North America and Europe.Patients with phenylketonuria were eligible to participate if they were ≥8 years of age and had received ≥80% of the scheduled doses in a previous 6-week, randomized, placebo-controlled study or had been withdrawn from that study after exceeding a plasma phenylalanine concentration of ≥1500 μmol/L to ≥1800 μmol/L, depending on the subject’s age and baseline plasma phenylalanine concentration. A total of 78 patients participated. Patients received oral once-daily doses of sapropterin (Kuvan®) 5, 10 or 20 mg/kg/day.Blood samples for the pharmacokinetic analysis were obtained during weeks 6, 10 and 12. A D-optimal sparse sampling strategy was used, and data were analysed by population-based, nonlinear, mixed-effects modelling methods. Main outcome measure: In a prospectively planned analysis, the apparent clearance, apparent volume of distribution, absorption rate constant and associated interindividual variabilities of each parameter were estimated by modelling observed BH4 plasma concentration-time data. Results: The best structural model to describe the pharmacokinetics of sapropterin was a two-compartment model with first-order input, first-order elimination and a baseline endogenous BH4 concentration term. Total bodyweight was the only significant covariate identified, the inclusion of which on both the apparent clearance (mean = 2100 L/h/70 kg) and central volume of distribution (mean = 8350 L/70 kg) substantially improved the model’s ability to describe the data. The mean (SD) terminal half-life of sapropterin was 6.69 (2.29) hours and there was little evidence of accumulation, even at the highest dose. Conclusion: These findings, taken together with the observed therapeutic effect, support bodyweight-based, once-daily dosing of sapropterin 5–20 mg/kg/day.

Population Pharmacokinetics and Exposure‐response Relationship of Enfuvirtide in Treatment‐experienced Human Immunodeficiency Virus Type 1—infected Patients

Our objective was to characterize population pharmacokinetics of enfuvirtide, 90 mg twice daily injected subcutaneously, in treatment‐experienced human immunodeficiency virus type 1 (HIV‐1)–infected patients, as well as the relationship between exposure and antiviral effect.

A Real-life Population Pharmacokinetic Study Reveals Factors Associated with Clearance and Immunogenicity of Infliximab in Inflammatory Bowel Disease.

Background: Several factors influencing the pharmacokinetics of infliximab (IFX) in inflammatory bowel disease (IBD) have been identified. We studied the impact of patient, disease, and treatment characteristics on clearance and immunogenicity of IFX in a real-world patient-with-IBD cohort. Methods: Serum concentrations of IFX and antibodies to IFX (ATIs) were measured in patients with IBD at a single center using an enzyme-linked immunosorbent assay and radioimmunoassay. Patient, disease, and treatment characteristics were retrospectively collected along with laboratory values. Pharmacokinetics and ATI titer were analyzed simultaneously by nonlinear mixed-effects modeling. Results: Nine hundred ninety-seven IFX concentrations and 756 ATI measurements from 332 patients with IBD (253 Crohns disease and 79 ulcerative colitis) were included. Mean (SD) IFX dose was 5.47 ± 1.33 mg/kg. ATIs were detected in 75/332 (23%) patients; insufficient exposure below an IFX trough level of 3 &mgr;g/mL was the most predictive factor of developing ATI and resulted in a 4-fold increased risk of ATI development. ATI titer was a better predictor of IFX clearance than ATI as a dichotomous parameter. ATI titers >30 AU/mL were consistently associated with undetectable IFX concentrations. IFX clearance was affected by body weight (40–149 kg) ranging from 0.27 to 0.53 L/d, serum albumin (2–5.4 g/dL) from 0.93 to 0.24 L/d, and titers of ATIs (0–53,000 AU/mL) from 0.36 L/d to 15.93 L/d (P < 0.001). Previously biologic-treated patients exhibited a higher clearance of IFX. Conclusions: IFX exposure below 3 &mgr;g/mL increases risk of ATIs. Identification of influential pharmacokinetics and ATI factors improves prediction of IFX levels, potentially allowing individualized dosing and cost reduction.