Body Weight-based Dosing Research Articles

Pediatric Dosing of Intravenous Sotalol Based on Body Surface Area in Patients with Arrhythmia

In a recently published study, we evaluated the efficacy and safety of intravenous sotalol in pediatric patients with incessant tachyarrhythmias and we have found that intravenous sotalol is effective and safe. Our dosing regimen was based on the body weight of the patients. In the US, the recommendation for intravenous sotalol dosing in pediatric patients is based on body surface area (BSA) while taking into consideration the patients’ age. The purpose of this paper is to show the correspondence of a body weight-based dosing regimen when expressed for BSA as mg/m2. We evaluated the similarity of a body weight-based dose to that calculated based on BSA using the US labeling recommendations. Of the 83 patients, 5 were newborns (age: 0–30 days), 39 infants and toddlers (age: 1–24 month), 26 young children (age: >2–6 years), 11 older children (age: 6–12 years), and 2 adolescents (age: 14 years). Each received a loading dose of 1 mg/kg intravenous sotalol administered over 10 min followed by a maintenance dose of 4.5 mg/kg/day. There was a close correlation between the sotalol loading doses calculated based on body weight and BSA across the entire age range (r = 0.977, p < 0.001). In most of the age groups, the body weight-based loading doses were lower or equal to the BSA-based doses. Only in the adolescents were the body weight-based doses higher. The maintenance doses given in our study were significantly higher than the BSA-based dose in newborns: 75 ± 6 versus 53 ± 8 mg/m2, p < 0.05; infants/toddlers: 88 ± 14 versus 77 ± 7 mg/m2, p < 0.001; younger children: 113 ± 12 versus 85 mg/m2, p < 0.001; older children: 123 ± 16 versus 85 mg/m2, p < 0.01; and adolescents 157 ± 30 versus 85.5 mg/m2. Despite the rapid administration of the loading dose and the increased maintenance doses, our body weight-based dosing regimen was safe. Only one newborn had significant adverse event (AV block) that resolved spontaneously after discontinuation of the infusion.

Population Pharmacokinetic Analysis of Zolmitriptan and Its Metabolite in Adults and Adolescents to Support Dose Selection in Children With Migraine.

Zolmitriptan is a serotonin (5-HT) 1B/1D receptor agonist effective for the treatment of migraine. This analysis aimed to develop a population pharmacokinetic (PK) model for zolmitriptan and its active metabolite in adults and adolescents and provide appropriate dosing regimens to be used in clinical trials for children 6-11 years old. The data from a single-dose clinical study of 5.0-mg zolmitriptan nasal spray (ZNS) conducted in adult and adolescent patients with migraine between migraine attacks was applied. Similar plasma concentration profiles of zolmitriptan and its metabolite, 183C91, were observed in adults and adolescents. A 1-compartment model with first-order absorption and first-order elimination reasonably described the zolmitriptan PK. With a portion of elimination of zolmitriptan being treated as the conversion from zolmitriptan to 183C91, the disposition of 183C91 was described by a 1-compartment model with first-order elimination. The estimated typical apparent volume of distribution and clearance of zolmitriptan were 136 L and 121 L/h, respectively, with 56.5% and 42.6% between-subject variability, respectively. Based on the simulation results with the final population PK model, a body weight-based dosing scheme of 5.0 and 2.5 mg ZNS in children greater than and less than 50 kg is recommended to achieve exposures similar to those of the adult and adolescent population administered 5.0 mg ZNS. The recommended doses for children to achieve exposure similar to that observed in adults given 2.5 mg ZNS are 2.5mg (≥50 kg) and 1.0 mg (15-50 kg). These dosing regimens could be used in future clinical trials.

Overweight Kidney Transplant Recipients Are at Risk of Being Overdosed Following Standard Bodyweight-Based Tacrolimus Starting Dose.

BackgroundBodyweight-based dosing of tacrolimus (Tac) is considered standard care, even though the available evidence is thin. An increasing proportion of transplant recipients is overweight, prompting the question if the starting dose should always be based on bodyweight.MethodsFor this analysis, data were used from a randomized-controlled trial in which patients received either a standard Tac starting dose or a dose that was based on CYP3A5 genotype. The hypothesis was that overweight patients would have Tac overexposure following standard bodyweight-based dosing.ResultsData were available for 203 kidney transplant recipients, with a median body mass index (BMI) of 25.6 (range, 17.2-42.2). More than 50% of the overweight or obese patients had a Tac predose concentration above the target range. The CYP3A5 nonexpressers tended to be above target when they weighed more than 67.5 kg or had a BMI of 24.5 or higher. Dosing guidelines were proposed with a decrease up to 40% in Tac starting doses for different BMI groups. The dosing guideline for patients with an unknown genotype was validated using the fixed-dose versus concentration controlled data set.ConclusionsThis study demonstrates that dosing Tac solely on bodyweight results in overexposure in more than half of overweight or obese patients.

Morbid Obesity Alters Both Pharmacokinetics and Pharmacodynamics of Propofol: Dosing Recommendation for Anesthesia Induction.

The prevalence of obesity has markedly increased worldwide. Obese patients pose significant challenges to anesthesiologists with regard to accurate dosing of anesthetics due to potentially altered pharmacokinetics (PK). Here we determined the PK and pharmacodynamics (PD) of propofol for anesthesia induction in morbidly obese (MO) subjects (body mass index >35 kg/m(2)) at two dosing regimens: dosing based on total body weight and lean body weight (LBW), respectively. The propofol pharmacokinetic profile was well fitted with a two-compartment model. Both elimination clearance (223%-243% of controls, who had a body mass index <25 kg/m(2); P < 0.01) and peripheral compartment volume (156%-180% of controls; P < 0.01) were significantly increased in MO subjects, resulting in an equal or decreased propofol level in plasma (total body weight-based dosing). Furthermore, propofol PD (measured by the bispectral index) was adequately described by a PK/PD model that linked an effect compartment to the two-compartment PK model through a sigmoidal Emax model. All PD parameters except EC50 values (the half maximal effect concentration) were similar (P > 0.05) between MO subjects and controls. Morbid obesity led to a significant decrease (37.9%-38.6%; P < 0.01) in EC50 values, which suggests increased brain sensitivity to propofol in the MO population. Moreover, dose reduction (i.e., dosing based on LBW) generated identical anesthetic effects in MO subjects compared with controls. In conclusion, morbid obesity significantly altered both PK and PD of propofol. LBW was a better weight-based dosing scalar for anesthesia induction with propofol in MO subjects.

Exposure-Response Analysis to Assist Selection of Dose and Treatment Duration for Polatuzumab Vedotin As a Single Agent or in Combination with Rituximab for the Treatment of B-Cell Lymphoma

IntroductionPolatuzumab vedotin (PoV), an antibody-drug-conjugate containing the microtubule inhibitor monomethyl auristatin E (MMAE), is in development for the treatment of B-cell lymphoma (BCL). In phase 1 and 2 studies assessing PoV alone or in combination with rituximab (RTX), PoV treatment until disease progression was associated with high discontinuation rates due to peripheral neuropathy (PN) at the dose of 2.4 mg/kg. Therefore, dose and schedule optimization, including justification of body weight-based dosing, dose capping, and selection of dose level and treatment durations, were evaluated to maximize efficacy and reduce the rate of treatment-emergent PN.MethodsPopulation pharmacokinetics (Pop-PK) for antibody-conjugated MMAE (acMMAE) and exposure-response (E-R) analyses were conducted. A Pop-PK model was developed including clinically relevant covariates recorded in phase 1 and 2 studies of PoV administered every 3 weeks (N=155; Table 1). A simulation was performed to compare acMMAE PK variability with body weight-based vs. fixed dosing. Exposure to acMMAE was also simulated in patients ≥101.9 kg (90th percentile of body weight) receiving a hypothetical capped PoV dose of 240 mg. E-R analyses were stratified by histology, with efficacy based on overall response (OR, complete or partial response per revised IWG criteria [Cheson et al. 2007]) and safety based on the incidence of grade ≥2 PN. Logistic regression and time-to-event analyses were conducted. E-R analyses were also performed to compare safety and efficacy through 8 cycles of treatment vs. treatment discontinuation for disease progression or unacceptable toxicity.ResultsPop-PK analysis for acMMAE identified body weight as a significant covariate for both clearance (CLinf) and central volume of distribution (Vc). Simulation suggested that body weight-based dosing (2.4 mg/kg) would result in much lower PK variability than fixed dosing (185.5 mg), with a trend towards slightly higher exposure for patients ≥101.9 kg (Figure 1). This trend of higher exposure was not observed if the PoV dose was capped to 240 mg for these patients.E-R analyses suggested that higher acMMAE exposure was associated with increased likelihood of OR for patients with indolent BCL (including follicular, marginal zone, and small lymphocytic lymphomas; Figure 2) or diffuse large BCL (DLBCL). When acMMAE exposure was translated to the PoV dose, the covariate-adjusted odds ratio (90% confidence interval [CI]) of OR for PoV 2.4 vs. 1.8 mg/kg was 1.73 (1.29-1.74) and 2.39 (1.43-6.13) for indolent BCL and DLBCL, respectively. The effect of adding RTX on PoV efficacy was not statistically significant. Grade ≥2 PN incidence increased with acMMAE exposure for both indolent BCL (Figure 2) and DLBCL. Furthermore, time-to-event analysis indicated that the rate of grade ≥2 PN increased with treatment duration.Based on safety and efficacy through 8 cycles of treatment, the incidence of grade ≥2 PN was decreased, while the higher OR probability for 2.4 mg/kg dose was maintained in both indolent BCL (Figure 2) and DLBCL patients. The time-to-event analysis suggested that treatment with ≤8 cycles of PoV resulted in a model-predicted incidence (90% CI) of grade ≥2 PN events of 28.9% (21.3-34.7%) and 35.1% (26.2-41.7%) for 1.8 and 2.4 mg/kg, respectively.ConclusionsBody weight-based dosing for all patients with capping the PoV dose at 240 mg for heavy patients (≥101.9 kg) provides lower PK variability for all patients than fixed dosing and may mitigate potential safety risks for heavy patients. When given alone or in combination with RTX, a PoV dose of 2.4 mg/kg is associated with a higher likelihood of achieving an OR compared with 1.8 mg/kg. Capping treatment to ≤8 cycles may mitigate treatment-emergent PN risk. Thus, selection of PoV dose and/or capping of treatment duration may offer an optimal benefit-risk profile. Current clinical studies are testing PoV 1.8 mg/kg limited to 6-8 cycles to further mitigate safety risk when given in combination with immunochemotherapy or novel small molecule pathway inhibitors. Future clinical testing at the 2.4 mg/kg dose level may also be warranted. [Display omitted] [Display omitted] [Display omitted] DisclosuresLu:Genentech, Inc.: Employment, Equity Ownership. Off Label Use: Polatuzumab vedotin is an investigational agent and not approved in B-cell lymphoma. Jin:Genentech, Inc.: Employment. Gibiansky:Genentech, Inc.: Consultancy. Gillespie:Genentech, Inc.: Consultancy. Agarwal:Genentech, Inc.: Employment. Jones:Genentech, Inc.: Employment. Chu:Genentech, Inc.: Employment. Wenger:Genentech, Inc.: Employment. Hirata:Genentech, Inc.: Employment, Equity Ownership. Li:Genentech, Inc.: Employment. Girish:Genentech, Inc.: Employment.

Target-Mediated Drug Disposition of Daratumumab Following Intravenous Infusion in Relapsed or Refractory Multiple Myeloma after Prior Proteasome Inhibitors and Immunomodulatory Drugs: A Population Pharmacokinetic Analysis

Introduction: Daratumumab is a first-in-class human anti-CD38 IgG1 monoclonal antibody in clinical development across the multiple myeloma (MM) disease spectrum. A population pharmacokinetics (PK) analysis was conducted (1) to characterize the target-mediated drug disposition (TMDD) and the variability associated with daratumumab disposition, (2) to evaluate the effects of individual demographic characteristics and other factors (e.g., laboratory tests and baseline disease status) on the disposition of daratumumab, (3) to understand daratumumab exposure in special populations (e.g., patients with renal or hepatic impairment and elderly patients), and (4) to predict target saturation and its relationship with daratumumab exposure.Methods: A total of 2,572 daratumumab concentration measurements from 223 patients enrolled in a Phase 1/2 study (GEN501 [NCT00574288]) and a Phase 2 study (MMY2002 [NCT01985126]) were included in the population PK modeling. Daratumumab doses ranged from 0.1 to 24 mg/kg, and 150 of these patients received 16 mg/kg. A mixed-effects 2-compartment pharmacokinetic model based on Michaelis-Menten approximation TMDD was developed. Model-based covariate analyses and simulations were conducted to evaluate the influence of individual characteristics/factors on exposure to daratumumab.Results: The population PK model suggested that the disposition of daratumumab was concentration- and dose-dependent, i.e., lower clearance at higher daratumumab concentrations. The model further revealed that the nonlinear concentration-dependent clearance decreased over time, which could be described as a first-order process. The concentration- and time-dependency of daratumumab clearance suggested that the dynamics of target/tumor burden significantly influenced daratumumab disposition in MM patients. The estimated target binding affinity (ie, concentration at 50% target saturation) was 2.38 µg/mL. The population PK model predicted that a concentration of 21.4 µg/mL and 236 µg/mL would be needed to achieve 90% and 99% target saturation, respectively. The estimated linear clearance (0.17 L/day) was very close to the clearance of non-specific endogenous IgG described in the literature and the volume of distribution of central compartment (V1) approached plasma volume, confirming the robustness of the model.The clearance and V1 of daratumumab significantly increased with increasing body weight. Consequently, exposure to daratumumab was relatively consistent across the range of body weights of MM patients after administration on a mg/kg basis. Age, race, renal impairment, and mild hepatic impairment had neither statistically significant nor clinically relevant effects on exposure to daratumumab. In addition, exposure was consistent across the different subgroups for performance status (ECOG), refractory status, and number of prior lines of therapy. Although baseline albumin levels, type of myeloma (IgG vs non-IgG), sex, and drug products had a statistically significant effect on daratumumab pharmacokinetics, further analyses demonstrated that these covariates had no clinically relevant impact on efficacy or safety profiles.Conclusion: The population PK model revealed a concentration- and time-dependent clearance of daratumumab, suggesting the presence of TMDD. A serum daratumumab concentration of 236 μg/mL was predicted to yield 99% target (CD38) saturation. This analysis suggests that body weight-based dosing is a feasible strategy for MM patients. No clinically relevant demographic or clinical characteristics were identified. Therefore, no dose adjustment based on these factors is recommended. DisclosuresYan:Janssen: Employment. Clemens:Janssen: Employment. Puchalski:Janssen: Employment. Lonial:Novartis: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Lokhorst:Genmab: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria. Orlowski:Millennium Pharaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acetylon Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Array Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Research Funding; Biotheryx: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Losic:Genmab A/S: Employment. Khan:Janssen: Employment. Jansson:Janssen: Employment. Ahmadi:Janssen: Employment. Lantz:Janssen: Employment. Perez Ruixo:Janssen: Employment. Zhou:Janssen: Employment. Xu:Janssen: Employment.

Assessing Safety and Efficacy of Lean Body Weight-Based intravenous Heparin Dosing in Obese and Morbidly Obese Patients

Assessing Safety and Efficacy of Lean Body Weight-Based intravenous Heparin Dosing in Obese and Morbidly Obese Patients

Vancomycin-Associated Nephrotoxicity: The Obesity Factor.

Current recommendations suggest that vancomycin dosing utilize actual rather than ideal body weight in obese patients. Thus, obese patients may be at greater risk for nephrotoxicity. The purpose of this study was to compare the incidence of nephrotoxicity in vancomycin-treated obese and lean patients at our institution, where unadjusted, actual body weight-based dosing (capped at 2 g per dose twice daily) is used. We expected obese patients to experience a greater incidence of nephrotoxicity than lean patients. This study examined a retrospective cohort of patients treated with vancomycin for gram-positive or mixed infections in our facility from 2005-2009 who were not receiving hemodialysis at the time of admission. Patients were stratified by body mass index (BMI; obese ≥30 kg/m(2) vs. lean <30 kg/m(2)). Relative risk (RR), 95% confidence intervals (CIs), and p values were computed using a generalized estimating equation to accommodate a correlated data structure corresponding to multiple episodes of infection per individual. Multivariable analysis was performed. A total of 530 patients (207 obese; 323 lean) with 1,007 episodes of infection were treated with vancomycin. Patient demographics, co-morbidities, sites of infection, and infecting organisms were similar in the two groups. Female gender (p=0.042), diabetes mellitus (DM) (p=0.018), and hypertension (HTN) (p=0.0009) were more often associated with obesity, whereas allografts (p=0.022) and peripheral vascular disease (p=0.036) were more often present in lean patients. The Acute Physiology and Chronic Health Evaluation II score >21 was the only variable associated with nephrotoxicity (p=0.039). After adjusting for statistically significant variables, obesity was found not to be associated with a greater risk of nephrotoxicity (RR=0.98; 95% CI=0.93-1.04; p=0.59). No difference in nephrotoxicity was observed between lean and obese patients treated with vancomycin at our institution.

Quantitative clinical pharmacology for size and age scaling in pediatric drug development: A systematic review

The establishment of drug dosing in children is often hindered by the lack of actual pediatric efficacy and safety data. To overcome this limitation, scaling approaches are frequently employed to leverage adult clinical information for informing pediatric dosing. The objective of this review is to provide a comprehensive overview of the different scaling approaches used in pediatric pharmacotherapy as well as their proper implementation in drug development and clinical use. We will start out with a brief overview of the current regulatory requirements in pediatric drug development, followed by a review of the most commonly employed scaling approaches in increasing order of complexity ranging from simple body weight-based dosing to physiologically-based pharmacokinetic (PBPK) modeling approaches. Each of the presented approaches has advantages and limitations, which will be highlighted throughout the course of the review by the use of clinically-relevant examples. The choice of the approach employed consequently depends on the clinical question at hand and the availability of sufficient clinical data. The main effort while establishing and qualifying these scaling approaches should be directed towards the development of safe and effective dosing regimens in children rather than identifying the best model, ie models should be fit for purpose.

Challenges and considerations for development of therapeutic proteins in pediatric patients.

Target specificity and generally good tolerability of therapeutic proteins (TPs) present desirable treatment opportunities for pediatric patients. However, little is known on the ontogeny of processes related to the pharmacokinetics (PK) and disposition of TPs. The science, regulatory requirements and strategy of developing TPs for children are evolving. Our current review of TPs, (with focus on monoclonal antibodies and fusion proteins) that were approved for pediatric use indicates that dose-selection for pediatric pivotal studies is often based on adult PK information alone. This approach might not be sufficient if more complex PK properties than simple linear PK are present. Body weight-based dosing for pediatric patients directly scaled down from adult dosing can lead to under-exposure in young pediatric patients who are usually in the lowest body-weight range. Tiered-fixed dosing can be reasonably effective for TPs in achieving comparable exposure in children over a wide age range. The uniqueness of the pediatric population, the practical challenges in conducting clinical studies in this population, as well as regulations from health authorities warrant including pharmacometrics as an integral component of pediatric drug development. We propose a framework distinct from previous proposals, to guide clinical pharmacology strategy for pediatric drug development specifically for TPs.

Pharmacokinetics of hydrocodone/acetaminophen combination product in children ages 6-17 with moderate to moderately severe postoperative pain

Lortab® Elixir, a proprietary combination product containing hydrocodone and acetaminophen, is approved in the US for the treatment of moderate to moderately severe pain in children. Despite this approval, pediatric pharmacokinetic data using this product have not been previously published. Using a single-dose open-label study approach, we evaluated the pharmacokinetics, tolerability, and safety of this product in 17 healthy children 6-17 years of age. Results showed that the body weight-normalized oral clearance (L/h/kg) of hydrocodone and acetaminophen were 42% and 27% higher, respectively when compared to data from healthy adults. This suggests that a higher mg/kg dose would be required in children to achieve exposures similar to adults. We found adjustment of hydrocodone and acetaminophen dose by body surface area to be more optimal than body weight-based dose adjustments for achieving similar systemic exposure in children and adults. However, body weight-based hydrocodone and acetaminophen dosing regimens provided close approximation of adult exposures in pediatric patients with approximately 22% to 24% lower hydrocodone and acetaminophen dose/BW-normalized AUC in pediatric patients compared to adults. Finally, the adverse event profile in our pediatric cohort was consistent with that expected of opioid-naive subjects receiving opioid-combination therapy.

Pharmacokinetics and Pharmacodynamics of Anticoagulants in Paediatric Patients

Given the rising incidence of thrombotic complications in paediatric patients, understanding of the pharmacologic behaviour of anticoagulant drugs in children has gained importance. Significant developmental differences between children and adults in the haemostatic system and pharmacologic parameters for individual drugs highlight potentially unique aspects of anticoagulant pharmacology in this special and vulnerable population. This review focuses on pharmacologic information relevant to the dosing of unfractionated heparin, low molecular weight heparin, warfarin, bivalirudin, argatroban and fondaparinux in paediatric patients. The bulk of clinical experience with paediatric anticoagulation rests with the first three of these agents, each of which requires higher bodyweight-based dosing for the youngest patients, compared with adults, in order to achieve comparable pharmacodynamic effects, likely related to an inverse correlation between age and bodyweight-normalized clearance of these drugs. Whether extrapolation of therapeutic ranges targeted for adult patients prescribed these agents is valid for children, however, is unknown and a high priority for future research. Novel oral anticoagulants, such as dabigatran, rivaroxaban and apixaban, hold promise for future use in paediatrics but require further pharmacologic study in infants, children and adolescents.

Phase II results of tasisulam-sodium in previously treated patients with metastatic breast cancer.

114 Background: Tasisulam, a novel acylsulfonamide antineoplastic agent, promotes apoptosis, exhibits antiangiogenic activities, and demontrates antiproliferative activity against human breast cancer cell lines. In humans, tasisulam is highly albumin bound, with a median half-life of approximately 11 days. Previous phase II studies of tasisulam indicated that an albumin-corrected exposure (AUCalb) range of 1200 to 6400 h*mcg/mL provided the optimal balance of efficacy and safety. This study investigates the drug’s activity in previously treated patients (pts) with metastatic breast cancer (mBC). Methods: Pts with at least 2 prior therapies for mBC andserum albumin level ≥3.0 g/dL received tasisulam by 2-hour infusion every 28 days, dosed by a lean body weight-based dosing algorithm targeting an AUCalb range of 1200 to 6400 h*mcg/mL. Primary objective was to show at least a 10% response rate (RR) using RECIST 1.0. Secondary objectives included progression-free survival (PFS), overall survival (OS), pharmacokinetics (PK), and safety. Results: Thirty-three pts received at least 1 dose of tasisulam. All were women, with a mean age of 55.4 (±9.7) years. Pts received a median of 2 cycles (ranges 1-8). The majority of pts achieved the target AUCalb range of 1200 to 6400 h*mcg/mL or higher in cycles 1 and 2 (63% and 69%, respectively). The most common tasisulam-related hematologic toxicities were grade 3 anemia (3.0%) and grade 4 neutropenia (6.1%). Common nonhematological adverse events possibly related to tasisulam were fatigue (39.4%), diarrhea (24.2%), and nausea (18.2%). No deaths were considered related to the study drug. The RR (1 CR, 1 PR) was 6.1% (90% CI: 1.1, 17.9), stable disease rate was 24% (n=8; 90% CI: 12.7, 39.5), with a median PFS of 1.81 months (90% CI: 1.64, 2.17) and a median OS of 6.77 months (90% CI: 4.37, 11.63). Conclusions: Tasisulam was reasonably well tolerated, but did not meet its primary objective of overall RR of 10% in this heavily pretreated mBC patient population. PK analysis of the albumin-tailored dosing regimen indicated that the majority of the patients achieved the target AUCalb or higher, suggesting that the modest activity observed was not due to suboptimal dosing.

Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and children.

Although it has been on the market for over a decade, confusion remains regarding the pharmacokinetics (PK) and optimal dosing of palivizumab, a humanized IgG1κ monoclonal antibody indicated for the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of RSV disease. The objectives of this analysis were to characterize the population PK of palivizumab in adults and children using nonlinear mixed-effect modeling, quantify the effects of individual covariates on variability in palivizumab disposition, and compare palivizumab exposures for various dosing scenarios. Palivizumab PK data from 22 clinical studies were used for model development. The model was developed using a two-stage approach: (i) a 2-compartment model with first-order absorption after intramuscular administration was fitted to adult data, and (ii) the same structural model was fitted to the sparse pediatric data using the NONMEM $PRIOR subroutine, with informative priors obtained from the adult analysis. Body weight and an age descriptor that combines gestational age and postnatal age (PAGE) using an asymptotic-exponential model best described palivizumab clearance in pediatric patients. Palivizumab clearance increased slightly from 10.2 ml/day to 11.9 ml/day as a function of PAGE ranging from 7 to 18 months. Covariate analysis indicated a 20% higher clearance in children with chronic lung disease and in children with antidrug antibody titer values of ≥80. These covariates did not substantially explain interindividual variability. In the label-indicated pediatric population, body weight was the primary demographic factor affecting palivizumab PK. Body weight-based dosing of 15 mg/kg yields similar palivizumab concentrations in children of different gestational and postnatal ages. Simulations demonstrated that there was little difference in palivizumab PK between healthy term and premature infants. Simulations also demonstrated that the 5 monthly palivizumab doses of 15 mg/kg, consistent with the label and studied in two randomized, clinical trials, provided greater and more prolonged palivizumab exposure than did an abbreviated dosing regimen of 3 monthly doses.

Clinical Implications of Pathophysiological and Demographic Covariates on the Population Pharmacokinetics of Trastuzumab Emtansine, a HER2‐Targeted Antibody‐Drug Conjugate, in Patients With HER2‐Positive Metastatic Breast Cancer

Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate in development for treatment of HER2-positive cancers. T-DM1 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer (MBC), with the maximum tolerated dose established at 3.6 mg/kg intravenously for every-3-week dosing. The authors present results from the population pharmacokinetics analysis for T-DM1. Population pharmacokinetics for T-DM1 were characterized using a clinical database of 273 patients from the 3 studies. Pharmacokinetics was best described by a linear 2-compartment model. Population estimates (interindividual variability [IIV]) for pharmacokinetic parameters were clearance, 0.7 L/d (21.0%); central compartment volume (V(c)), 3.33 L (13.2%); peripheral compartment volume (V(p)), 0.89 L (50.4%); and intercompartmental clearance, 0.78 L/d. Body weight, albumin, tumor burden, and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in T-DM1 pharmacokinetics, with body weight having a greater effect on IIV of clearance and V(c) than other covariates. T-DM1 exposure was relatively consistent across the weight range following body weight-based dosing. This analysis suggests no further T-DM1 dose adjustments are necessary in heavily pretreated patients with MBC.

A phase II study of tasisulam sodium (LY573636 sodium) as second-line or third-line treatment for patients with unresectable or metastatic soft tissue sarcoma

Tasisulam sodium (hereafter tasisulam), a novel anticancer agent, is being studied in a broad range of tumors. The primary objective of this phase II study was to determine progression-free survival (PFS) in patients with 1 or 2 prior chemotherapy regimens for unresectable/metastatic soft tissue sarcoma (STS). Secondary objectives included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), pharmacokinetics, and safety. Tasisulam was administered intravenously on day 1 of 21-day cycles according to a lean body weight-based dosing algorithm targeting a peak plasma concentration (C(max)) of 420 μg/mL; a 360-μg/mL dose level was also explored. The median age of patients treated at 420 μg/mL was 58.3 years (range, 18.6-80.4; n = 63). Median PFS was 2.64 months (90 % CI, 1.41-3.38), with a 6-month PFS rate of 11 % (90 % CI, 4-17). Median OS was 8.71 months (90 % CI, 7.39-16.23); ORR, 3.2 %; and CBR, 46.0 % (stable disease, n = 27; partial response/confirmed, n = 2 [angiosarcoma and leiomyosarcoma]; partial response/unconfirmed, n = 1 [desmoplastic small round cell tumor]). The most frequent drug-related grade 3/4 toxicities in patients treated at 420 μg/mL were thrombocytopenia (27.0 %) and neutropenia (22.2 %). Incidences of grade 4 thrombocytopenia and/or neutropenia were 20.6 % in patients treated at 420 μg/mL and 15.8 % in those treated at 360 μg/mL (n = 38). Tasisulam at a target C(max) of 420 μg/mL on day 1 of 21-day cycles demonstrated modest activity as second-/third-line treatment in patients with STS. Grade 4 hematologic toxicity posed some challenges in these heavily pre-treated patients. Tasisulam dosing continues to be refined.

Levothyroxine dose following thyroidectomy is affected by more than just body weight

To determine the factors that affect levothyroxine (LT4) requirements following thyroidectomy. Retrospective study. This study evaluated 246 participants who had undergone total thyroidectomy and were on a stable dose of LT4. Actual weight-based (AWB) and ideal body weight-based (IBWB) LT4 dose requirements were analyzed, and other confounders including adherence, concurrent medications, comorbidities, female menopausal status, and hormone replacement therapy were examined. A total of 205 women and 41 men were evaluated, with 48 (20%) benign and 198 (80%) malignant pathology findings. The mean AWB LT4 doses for men and premenopausal women were similar among members of the benign groups and similar among members of the malignant groups. There was a trend for lower dose LT4 in postmenopausal women off hormonal therapy (PM/NH) and on hormonal therapy (PM/H) in the benign group (1.4 and 1.6 μg/kg vs. 1.8 μg/kg in the men and premenopausal women) and a trend for lower dose LT4 in the PM/H women in the malignant group (1.9 μg/kg vs. 2.1 and 2.2 μg/kg in the men and premenopausal women), but they were not significant. However, PM/NH women required significantly less LT4 (1.7 μg/kg) than both the men (2.2 μg/kg) and premenopausal women (2.1 μg/kg) in the malignant group (P=.0006). The IBWB LT4 dosage was not statistically different between groups. LT4 dosage following thyroidectomy, calculated using actual body weight, can range from 1.4 to 2.2 μg/kg and is dependent on diagnosis (benign vs. malignant), goal TSH, sex, and menopausal status.

A Guide to Rational Dosing of Monoclonal Antibodies

Dosing of therapeutic monoclonal antibodies (mAbs) is often based on body size, with the perception that body size-based dosing would reduce inter-subject variability in drug exposure. However, most mAbs are target specific with a relatively large therapeutic window and generally a small contribution of body size to pharmacokinetic variability. Therefore, the dosing paradigm for mAbs should be assessed in the context of these unique characteristics. The objective of this study was to review the current dosing strategy and to provide a scientific rationale for dosing of mAbs using a modelling and simulation approach. In this analysis, the body weight-based or body weight-independent (fixed) dosing regimens for mAbs were systematically evaluated. A generic two-compartment first-order elimination model was developed. Individual or population pharmacokinetic profiles were simulated as a function of the body weight effects on clearance (θ(BW_CL)) and on the central volume of distribution (θ(BW_V1)). The variability in exposure (the area under the serum concentration-time curve [AUC], trough serum concentration [C(min)] and peak serum concentration [C(max)]) was compared between body weight-based dosing and fixed dosing in the entire population. The deviation of exposure for light and heavy subjects from median body weight subjects was also measured. The simulation results were then evaluated with clinical pharmacokinetic characteristics of various mAbs that were given either by body weight-based dosing or by fixed dosing in the case study. Results from this analysis demonstrated that exposure variability was dependent on the magnitude of the body weight effect on pharmacokinetics. In contrast to the conventional assumption, body weight-based dosing does not always offer advantages over fixed dosing in reducing exposure variability. In general, when the exponential functions of θ(BW_CL) and θ(BW_V1) in the population pharmacokinetic model are <0.5, fixed dosing results in less variability and less deviation than body weight-based dosing; when both θ(BW_CL) and θ(BW_V1) are >0.5, body weight-based dosing results in less variability and less deviation than fixed dosing. In the scenarios when either θ(BW_CL) or θ(BW_V1) is >0.5, the impact on exposure variability is different for each exposure measure. The case study demonstrated that most mAbs had little effect or a moderate body weight effect (θ(BW_CL) and θ(BW_V1) <0.5 or ∼0.5). The difference of variability in exposure between body weight-based and fixed dosing is generally less than 20% and the percentages of deviation for light and heavy subpopulations are less than 40%. The analysis provided insights into the conditions under which either fixed or body weight-based dosing would be superior in reducing pharmacokinetic variability and exposure differences between light and heavy subjects across the population. The pharmacokinetic variability introduced by either dosing regimen is moderate relative to the variability generally observed in pharmacodynamics, efficacy and safety. Therefore, mAb dosing can be flexible. Given many practical advantages, fixed dosing is recommended to be the first option in first-in-human studies with mAbs. The dosing strategy in later stages of clinical development could then be determined based on combined knowledge of the body weight effect on pharmacokinetics, safety and efficacy from the early clinical trials.

Population Pharmacokinetic Meta-Analysis of Denosumab in Healthy Subjects and Postmenopausal Women with Osteopenia or Osteoporosis

Inhibition of the receptor activator of nuclear factor κ-B ligand (RANKL) is a therapeutic target for treatment of bone disorders associated with increased bone resorption, such as osteoporosis. The objective of this analysis was to characterize the population pharmacokinetics of denosumab (AMG 162; Prolia®), a fully human IgG2 monoclonal antibody that binds to RANKL, in healthy subjects and postmenopausal women with osteopenia or osteoporosis. A total of 22944 serum free denosumab concentrations from 495 healthy subjects and 1069 postmenopausal women with osteopenia or osteoporosis were pooled. Denosumab was administered as either a single intravenous dose (n = 36), a single subcutaneous dose (n = 469) or multiple subcutaneous doses (n = 1059), ranging from 0.01 to 3 mg/kg (or 6-210 mg as fixed mass dosages), every 3 or 6 months for up to 48 months. An open, two-compartment pharmacokinetic model with a quasi-steady-state approximation of the target-mediated drug disposition model was used to describe denosumab pharmacokinetics, using NONMEM Version 7.1.0 software. Subcutaneous absorption was characterized by the first-order absorption rate constant (k(a)), with constant absolute bioavailability over the range of doses that were evaluated. Clearance and volume of distribution parameters were scaled by body weight, using a power model. Model evaluation was performed through visual predictive checks. The subcutaneous bioavailability of denosumab was 64%, and the k(a) was 0.00883 h-1. The central volume of distribution and linear clearance were 2.49 L/66 kg and 3.06 mL/h/66 kg, respectively. The baseline RANKL level, quasi-steady-state constant and RANKL degradation rate were 614 ng/mL, 138 ng/mL and 0.00148 h-1, respectively. Between-subject variability in model parameters was moderate. A fixed dose of 60 mg provided RANKL inhibition similar to that achieved by equivalent body weight-based dosing. The effects of age and race on the area under the serum concentration-time curve of denosumab were less than 15% over the range of covariate values that were evaluated. The non-linearity in denosumab pharmacokinetics is probably due to RANKL binding, and denosumab dose adjustment based on the patient demographics is not warranted.

Dose-finding Study of Peginesatide for Anemia Correction in Chronic Kidney Disease Patients

Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent. We report the first assessment of its efficacy and safety in correcting renal anemia in a population of 139 nondialysis chronic kidney disease patients. Chronic kidney disease patients who were not on dialysis and not receiving treatment with erythropoiesis-stimulating agents in the 12 weeks before study drug administration were sequentially assigned to one of 10 cohorts; cohorts differed in starting peginesatide dose (different body weight-based or absolute doses), route of administration (intravenous or subcutaneous), and frequency of administration (every 4 or 2 weeks). Across all cohorts, 96% of patients achieved a hemoglobin response. A dose-response relationship was evident for hemoglobin increase. Comparable subcutaneous and intravenous peginesatide doses produced similar hemoglobin responses. Rapid rates of hemoglobin rise and hemoglobin excursions >13 g/dl tended to occur more frequently with every-2-weeks dosing than they did with every-4-weeks dosing. The range of final median doses in the every-4-weeks dosing groups was 0.019 to 0.043 mg/kg. Across all cohorts, 20% of patients reported serious adverse events (one patient had a possibly drug-related serious event) and 81% reported adverse events (11.5% reported possibly drug-related events); these events were consistent with those routinely observed in this patient population. This study suggests that peginesatide administered every 4 weeks can increase and maintain hemoglobin in nondialysis chronic kidney disease patients. Additional long-term data in larger groups of patients are required to further elucidate the efficacy and safety of this peptide-based erythropoiesis-stimulating agent.