Chandrahas G. Sahajwalla

Implications of Obesity for Drug Therapy: Limitations and Challenges

Obesity has become a worldwide challenge with significant health and socioeconomic implications. One of the major implications is its impact on drug therapy. In order to gain a better understanding of this impact, we surveyed the regulatory guidances, the newly approved molecular entity drug products, and drug product labels in the Physicians Desk Reference. This review summarizes the findings of the survey along with the existing knowledge on pharmacokinetic and pharmacodynamic changes associated with obesity.

Application of pharmacokinetics–pharmacodynamics/clinical response modeling and simulation for biologics drug development†

Biologics, specifically monoclonal antibody (mAb) drugs, have unique pharmacokinetic (PK) and pharmacodynamic (PD) characteristics as opposed to small molecules. Under the paradigm of model-based drug development, PK-PD/clinical response models offer critical insight in guiding biologics development at various stages. On the basis of the molecular structure and corresponding properties of biologics, typical mechanism-based [target-mediated drug disposition (TMDD)], physiologically based PK, PK-PD, and dose-response meta-analysis models are summarized. Examples of using TMDD, PK-PD, and meta-analysis in helping starting dose determination in first-in-human studies and dosing regimen optimization in phase II/III trials are discussed. Instead of covering the entirety of model-based biologics development, this review focuses on the guiding principles and the core mathematical descriptions underlying the PK or PK-PD models most used.

Type 2 diabetes in pediatrics and adults: thoughts from a clinical pharmacology perspective.

Type 2 diabetes results when insulin secretion is unable to keep the plasma glucose levels as per acceptable range. This leads to chronic hyperglycemia and its associated microvascular complications such as renal impairment (diabetic nephropathy), retinal abnormalities (diabetic retinopathy), and autonomic, sensory, and motor neuropathies (diabetic neuropathy) and macrovascular disease. Historically, type 2 diabetes is well known as an adult-onset disease; however, lately, the incidence of the disease is reported to be increasing in children. Despite the wealth of information concerning type 2 diabetes in adults, data unique to the pediatric age group regarding the pathophysiology and therapy for type 2 diabetes are limited. For treatment in pediatric type 2 diabetes, metformin and insulin are the only antidiabetic agents approved currently. There are data of use of other oral antidiabetic drugs including glimepiride, rosiglitazone, and glyburide (in combination with metformin) in pediatric patients; however, formal clinical trials to establish the safety and efficacy have not been conducted. This review will compare the clinical pharmacology aspects of the oral type 2 diabetic drugs in pediatric and adult populations in order to determine any differences between the two patient groups.

Regulatory Review of Acetaminophen Clinical Pharmacology in Young Pediatric Patients

The acetaminophen dosage schedule in pediatric patients below 12 years of age for the over-the-counter (OTC) monograph is one of the many issues being evaluated and discussed in the development of the Proposed Rule for Internal Analgesic, Antipyretic, and Anti-rheumatic drug products. The dosage regimen based on age and weight, with instructions that weight-based dosage should be used if a childs weight is known, is currently being assessed by the agency. This review summarizes the available pharmacokinetic and pharmacodynamic (fever reduction) data of oral acetaminophen in pediatric patients of 6 months to 12 years of age. Acetaminophen is metabolized in the liver mainly through glucuronidation, sulfation, and to a lesser extent oxidation. Because of the difference in the ontogeny of various metabolizing pathways, the relative contribution of each pathway to the overall acetaminophen metabolism in children changes with age. The sulfation pathway plays a more important role in metabolizing acetaminophen than the glucuronidation pathway in younger children as compared with older children and adults. The pharmacokinetic exposure of acetaminophen in pediatric patients of 6 months to 12 years of age given oral administration of 10-15 mg/kg is within the adult exposure range given the OTC monograph dose. The antipyretic effect of acetaminophen is dose dependent and appears to be better than placebo at the dose range of 10-15 mg/kg in pediatric patients of 6 months to 12 years of age.

Kidney function changes with aging in adults: comparison between cross-sectional and longitudinal data analyses in renal function assessment.

The study evaluated whether the renal function decline rate per year with age in adults varies based on two primary statistical analyses: cross‐section (CS), using one observation per subject, and longitudinal (LT), using multiple observations per subject over time. A total of 16628 records (3946 subjects; age range 30–92 years) of creatinine clearance and relevant demographic data were used. On average, four samples per subject were collected for up to 2364 days (mean: 793 days). A simple linear regression and random coefficient models were selected for CS and LT analyses, respectively. The renal function decline rates per year were 1.33 and 0.95 ml/min/year for CS and LT analyses, respectively, and were slower when the repeated individual measurements were considered. The study confirms that rates are different based on statistical analyses, and that a statistically robust longitudinal model with a proper sampling design provides reliable individual as well as population estimates of the renal function decline rates per year with age in adults. In conclusion, our findings indicated that one should be cautious in interpreting the renal function decline rate with aging information because its estimation was highly dependent on the statistical analyses. From our analyses, a population longitudinal analysis (e.g. random coefficient model) is recommended if individualization is critical, such as a dose adjustment based on renal function during a chronic therapy. Copyright

Exposure–Response Modeling and Power Analysis of Components of ACR Response Criteria in Rheumatoid Arthritis (Part 2: Continuous Model)

Population pharmacokinetic/pharmacodynamic (PK/PD) models were developed to quantitate the exposure–response relationships using continuous longitudinal data on American College of Rheumatology (ACR) subcomponents, that is, tender‐joint count (TJC), swollen‐joint count (SJC), C‐reactive protein, patients assessment of pain, patients global assessment of disease activity, physicians global assessment of disease activity, and patients assessment of physical function for 5 biologics approved for use in rheumatoid arthritis. The models were then used to simulate the time courses of clinical outcomes following different treatment regimens. The relative sensitivity of the 7 subcomponents was assessed using Monte Carlo simulation–based power analysis. The developed population PK/PD models adequately described the relationship between serum concentrations and changes in ACR subcomponents. The trial simulation and subsequent power analysis showed that SJC and TJC appeared to be more sensitive than the other 5 ACR subcomponents to detect treatment effect over placebo/methotrexate. These 7 ACR subcomponents had similar power in detecting the treatment difference between different doses. In addition, the continuous measures of ACR subcomponents did not appear to be more sensitive than binary measures.

Use of a Systems Pharmacology Model Based Approach Toward Dose Optimization of Parathyroid Hormone Therapy in Hypoparathyroidism

We present an application of a quantitative systems pharmacology (QSP) model to support a regulatory decision, specifically in assessing the adequacy of the proposed dosing regimen. On January 23, 2015, the US Food and Drug Administration (FDA) approved Natpara (human parathyroid hormone (PTH)) to control hypocalcemia in patients with hypoparathyroidism. Clinical trial results indicated that although once‐daily PTH reduced calcium and vitamin D dose requirement while maintaining the normocalcemia, the regimen was not adequate to control hypercalciuria. We hypothesized that the lack of control on urinary calcium excretion was due to the short half‐life of PTH. The QSP model‐based simulations indicated that a more frequent dosing regimen may provide better control on hypercalciuria while maintaining normocalcemia. A postmarketing trial was recommended to assess pharmacokinetics (PKs) and pharmacodynamics (PDs) of PTH dose and dosing regimen. Although other modeling approaches may be feasible, in this specific case, QSP model‐based simulations fulfilled the information gap to support recommendations of this postmarketing trial.

Overview of recently approved 505(b)(2) new drug applications (2010-2012): role of clinical pharmacology.

The role of clinical pharmacology (CP) in the approval of 505(b)(2) NDAs was explored with the goal of sharing with the drug development community, some of the critical CP aspects that need to be considered and addressed during the planning and submission of a 505(b)(2) NDA. Among the 106 505(b)(2) NDAs approved in 2010–2012 (excluding those that were approved under the PEPFAR program), 25% included only CP information, no supportive clinical safety/efficacy was necessary for their approval and 43% included both clinical and CP information. A review of the pre‐submission interaction discussion held for 58% of the non‐PEPFAR NDAs, indicated that CP‐related aspects discussed at this avenue included study design of the pivotal BA/BE study, biowaiver related discussion, need for additional or supportive pharmacokinetic information to be included in the NDA, selection of the most appropriate reference drug product for 505(b)(2) purpose, as well as acceptability of publicly available information to address data gaps in knowledge. Further, we also noted that 505(b)(2) NDAs that did not report having a pre‐submission interaction with the Agency had twice the rate of receiving a complete response action in the first cycle as compared to the NDAs that did meet with the Agency.

The Role of the FDA in Guiding Drug Development

The drug development process is defined here as one that includes the preclinical and clinical phases of drug development following the selection of a lead molecule by the sponsor, and includes the regulatory review phase that is intended to lead to marketing authorization. This process is complex, time-consuming, and costly. A typical new molecular entity (NME), if approved for marketing, has gone through extensive preclinical pharmacology/toxicology evaluation followed by a clinical evaluation stage that lasts, on average, 5–7 years. With an average of 6–10 months required for regulatory review, the entire process, from preclinical evaluation to market approval, may take up to 15 years, with a cost that may exceed

On population pharmacokinetic model stability and performance

990 million dollars in direct and lost-opportunity costs. Given the current high attrition rate of drugs that enter into clinical testing (~50% in Phase III), the need for more predictive and informative drug development is obvious.