Regulatory Perspectives in Pharmacometric Models of Osteoporosis.

Osteoporosis is a disorder of the bones in which they are weakened to the extent that they become more prone to fracture. There are various forms of osteoporosis: some of them are induced by drugs, and others occur as a chronic progressive disorder as an individual gets older. As the median age of the population rises across the world, the chronic form of the bone disease is drawing attention as an important worldwide health issue. Developing new treatments for osteoporosis and comparing them with existing treatments are complicated processes due to current acceptance by regulatory authorities of bone mineral density (BMD) and fracture risk as clinical end points, which require clinical trials to be large, prolonged, and expensive to determine clinically significant impacts in BMD and fracture risk. Moreover, changes in BMD and fracture risk are not always correlated, with some clinical trials showing BMD improvement without a reduction in fractures. More recently, bone turnover markers specific to bone formation and resorption have been recognized that reflect bone physiology at a cellular level. These bone turnover markers change faster than BMD and fracture risk, and mathematically linking the biomarkers via a computational model to BMD and/or fracture risk may help in predicting BMD and fracture risk changes over time during the progression of a disease or when under treatment. Here, we discuss important concepts of bone physiology, osteoporosis, treatment options, mathematical modeling of osteoporosis, and the use of these models by the pharmaceutical industry and the Food and Drug Administration.

Exposure-Response of Palonosetron for Prevention of Chemotherapy-Induced Nausea and Vomiting in Pediatric Patients.

OBJECTIVES: Extrapolation of efficacy from adult populations to pediatrics may be appropriate if it is reasonable to assume that the 2 populations have similar disease progression and response to intervention. When full extrapolation of efficacy is deemed appropriate, the pediatric dose can be determined by "matching" exposure to a drug with that observed in adult patients. This approach has been used in certain therapeutic areas to alleviate the burden of pediatric clinical trials. We present here a case in which exposure matching is not appropriate. METHODS: Data analyses including pharmacokinetics and exposure-response were performed using data obtained from 2 pediatric chemotherapy-induced nausea and vomiting trials for intravenously administered palonosetron (Aloxi; a 5-HT3 receptor antagonist) injection and the results were compared with adult findings. RESULTS: At the approved doses for adults (0.25 mg) and pediatric patients (20 µg/kg), mean systemic exposure (area under the curve) of palonosetron in pediatric patients was approximately 3-fold higher than that in adults, whereas the response rate was similar between the 2 populations. Across pediatric patients, those younger than 6 years of age appeared to have a higher response than those ages 6 years or older, even though estimated systemic exposure was comparable between these age groups. CONCLUSIONS: Overall, these analyses provide an example in which pediatric and adult exposure data alone are insufficient to adequately identify effective pediatric doses and raise questions about the appropriateness of exposure matching for other drugs in the same therapeutic class. In such cases, pediatric dose-ranging and efficacy studies are needed.

Evaluating and Reporting the Immunogenicity Impacts for Biological Products--a Clinical Pharmacology Perspective.

Immunogenicity assessment is important for biological products due to potential impacts of immunogenicity on safety and efficacy. We reviewed the prescribing information and the FDA's clinical pharmacology review of 121 approved biological products for evaluating and reporting of immunogenicity data. Of the 121 products, 89% (n = 108) reported the incidence of immunogenicity and 49% (n = 59) reported immunogenicity impact on efficacy. However, only 26% (n = 31) reported whether the immunogenicity affected pharmacokinetics. A subset of 16 products reported effects of anti-drug antibodies (ADA) on both systemic clearance and efficacy; 8 of 16 products had increased systemic clearance coinciding with reduced efficacy, and 6 of 16 products had no changes in either clearance or efficacy. Factors contributing to infrequent reporting of the ADA effect on exposure and methods for determining the effect of ADA on exposure are summarized. Measuring ADA and drug concentrations concurrently over time enables the evaluation of ADA impact on pharmacokinetics. Within-subject comparison of concentration data (before vs. after ADA formation) is a useful alternative to between-subject (ADA+ vs. ADA-) comparison when sample size is limited or when the majority of subjects developed ADA. The biological complexity of immune responses presents challenges to quantifying the ADA impact on pharmacokinetics using model-based methods. Our findings support that pharmacokinetic exposure is more sensitive than efficacy endpoints for evaluating ADA effects. A decrease in drug concentration due to formation of ADA during treatment can serve as an early indicator for potential reduced efficacy occurring at a later time.

Biological products for the treatment of psoriasis: therapeutic targets, pharmacodynamics and disease-drug-drug interaction implications.

Psoriasis is a chronic inflammatory skin disease condition that involves altered expression of a broad spectrum of proinflammatory cytokines which are associated with activation of T cells and proliferation of keratinocytes. Currently approved biological products for psoriasis treatment fall into two main classes: cytokine modulators and biologics targeting T cells. In psoriatic patients, elevated levels of proinflammatory cytokines are observed. Elevated proinflammatory cytokines can suppress some cytochrome P450 (CYP) enzymes, and the treatment of psoriasis with biological products can reduce proinflammatory cytokine levels. Therefore, the exposure of CYP substrate drugs is anticipated to be affected by the psoriasis disease resulting in a higher exposure than in healthy state (named disease-drug interaction) as well as by the biological treatments due to disease improvements resulting in a decrease in exposure (named disease-drug-drug interaction, disease-DDI). However, the quantitative impact on CYP substrate exposure due to disease or due to treatment with biological products remains to be evaluated. The objective of the current review is to provide an overview of the therapeutic targets and cytokine-related pharmacodynamic effects of biological products in psoriasis treatment with a particular focus on their implications for disease-DDI. The clinical study design considerations for psoriasis disease-DDI evaluation are also discussed.

A survey of applications of biological products for drug interference of immunogenicity assays.

PURPOSE: Biological drugs in circulation can interfere with anti-drug antibody (ADA) assays and cause false ADA negatives. We surveyed the applications of biological products approved by FDA during 2005-2011 for prevalence of drug interferences and proposed approaches to address this issue scientifically. METHODS: The immunogenicity assay drug tolerance, steady-state drug concentrations, and immunogenicity rates were reviewed for 26 BLA/NDA and 2 sBLA. RESULTS: Many FDA approved biologics had higher steady-state drug concentrations than the drug tolerance of ADA assays, by 1.2- to 800-fold. Reported immunogenicity rates may be negatively impacted. Some sponsors triaged immunogenicity samples according to the drug tolerance, leaving some samples un-assayed or reporting them as inconclusive ADA; but these samples were interpreted as ADA- for calculating immunogenicity rates. CONCLUSIONS: Implementation of ADA assays that can tolerate therapeutic drug concentrations is imperative. Given drug interferences, we propose in this paper the following practices: (i) to measure drug concentrations in ADA samples, (ii) to explicitly list all ADA status, including inconclusive ADA and un-assayed samples, (iii) to calculate population immunogenicity rates based on only subjects with confirmed ADA+ and ADA-, and (iv) to make available ADA assay specifics relevant to the use of ADA data in disease management.

Using partial area for evaluation of bioavailability and bioequivalence.

Assessment of bioavailability/bioequivalence generally relies on the comparison of rate and extent of drug absorption between products. Rate of absorption is commonly expressed by peak concentration (C(max)) and time to peak concentration (T(max)), although these parameters are indirect measures of absorption rate. Recognizing the importance of systemic exposure to drug efficacy and safety, FDA recommended that systemic exposure be better used for bioavailability/bioequivalence assessment. Apart from peak exposure and total exposure, FDA also recommended a new metric for early exposure that is considered necessary when a control of input rate is critical to ascertain drug efficacy and/or safety profile. The early exposure can be measured by truncating the area under the curve at T(max) of the reference product (PAUC(r,tmax)) or some designated early time after dosing. The choice of truncation is most appropriately based on PK/PD relationship or efficacy/safety data for the drug under examination. Compared with C(max), PAUC(r,tmax) has higher sensitivity in detecting formulation differences and may be more variable. If the metric is highly variable, the reference-scaling approach can be employed for bioequivalence evaluation. The partial area metric is useful in PK/PD characterization as well as in the evaluation of bioavailability, bioequivalence and/or comparability.