Body Weight-based Dosing Research Articles

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.

Model-Based Approach for Optimization of Atazanavir Dose Recommendations for HIV-Infected Pediatric Patients

Atazanavir (Reyataz; ATV) is a well-tolerated protease inhibitor (PI) that is indicated as a once-daily treatment for HIV infections. These features of ATV, combined with its virologic potency, make it particularly desirable for the treatment of HIV-infected pediatric patients. The objective of this study was to use a model-based approach to recommend body weight-based ATV capsule doses for pediatric patients. ATV concentration-time data from three adult studies and one pediatric study were described by a C(0)-delinked one-compartment model to guard against introducing bias in pharmacokinetic (PK) parameter estimates due to the potential nonadherence in outpatient studies. The apparent clearance (CL/F) and apparent volume of distribution (V/F) were determined to increase with body weight, and CL/F was 40.9% lower in patients receiving ATV comedication with ritonavir (RTV). The relative bioavailability (F(rel)) of ATV was 132% higher with RTV comedication and was 35.5% lower for the ATV powder formulation than the capsule formulation. Model-based simulations were used to recommend weight-based ATV capsule doses of 150 to 300 mg boosted with 100 mg RTV for pediatric patients weighing ≥15 kg, such that the exposures in these patients are similar to those obtained in HIV-infected adults treated with the recommended ATV/RTV dose of 300/100 mg.

The Weight of Tissue Plasminogen Activator Dose in Overweight Patients With Strokes

See related article, page 1615–1620 Obesity is a widespread problem, particularly in the cardiovascular disease and stroke population. The combination of hypertriglyceridemia, glucose intolerance, and inflammation is linked with increased production of the primary inhibitor of endogenous thrombolysis, plasminogen activator inhibitor-1, leading to deficient thrombolysis in overweight patients. Enhanced fibrin crosslinking has been shown to be, at least partially, responsible for delayed clot lysis among obsesses. Moreover, body mass index was directly associated with fibrinogen, Factor VII, plasminogen activator inhibitor-1 and tissue plasminogen activator (tPA) antigen, von Willebrand factor, and viscosity. In contrast, body mass index itself had no impact on in-hospital mortality in patients undergoing primary percutaneous coronary interventions for acute myocardial infarction. Obese patients with acute myocardial infarction have a lower risk for in-hospital, 6-month, and 12-month mortality and cardiovascular events than patients with a normal body mass index.1 This “obesity paradox” may be explained by the fact that obese patients were younger at presentation. tPA dose for stroke (0.9 mg/kg alteplase, maximum 90 mg) was chosen based on small dose-escalation studies. This body weight-based dose has …

A phase 2 study of tasisulam sodium (LY573636 sodium) as second‐line treatment for patients with unresectable or metastatic melanoma

Tasisulam sodium (hereafter, tasisulam) is a novel anticancer agent that induces apoptosis through the intrinsic pathway and has antiangiogenic activity in preclinical models. Tasisulam demonstrated activity across a broad range of tumors, including melanoma. The primary objective of this phase 2 study was to determine the objective response rate (ORR) in patients who had received 1 previous systemic chemotherapy for unresectable/metastatic melanoma; secondary objectives were to evaluate the clinical response rate (CRR), progression-free survival (PFS), overall survival (OS), duration of response, safety, and pharmacokinetics. 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. In 68 enrolled patients, the median age was 59 years (range, 26-83 years). No patients had a complete response (CR), 8 patients had a partial response (PR), and 24 patients had stable disease (SD); the ORR (CR + PR) was 11.8%, and the CRR (CR + PR + SD) was 47.1%. The median PFS was 2.6 months, and the median OS was 9.6 months. The predominant treatment-related grade 3/4 toxicity was thrombocytopenia (20.6% of patients). Tasisulam exhibited a biexponential disposition with a predicted distribution half-life of 0.3 hours to 2.8 hours and a median terminal elimination half-life of 10 days (consistent with the turnover of albumin), suggesting that tasisulam is very tightly bound to albumin. Tasisulam administered at a targeted C(max) of 420 μg/mL on Day 1 of 21-day cycles demonstrated activity and tolerable toxicity as second-line treatment in malignant melanoma. These results led to a registration trial in metastatic melanoma.

Body Weight, Not Thrombus-Burden Tissue Plasminogen Activator Dosing

See related article, pages 2867–2871. After studies in cardiology that used body weight dosing, intravenous tissue plasminogen activator (tPA) dose for stroke (0.9 mg/kg alteplase, maximum 90 mg) emerged from small dose-escalation studies that started with doses far less than those for myocardial infarction.1 These studies were conducted before tests like CT angiography became readily available to determine thrombus location and extent in acute ischemic stroke. Current guidelines endorse this body weight-based dose as standard of care after pivotal randomized trials showed a significant benefit from systemic thrombolysis.2,3 During clinical trials and in daily practice, clinicians have to obtain body weight (actual or estimate) urgently when special beds equipped with calibrated scales are generally not available in emergency departments. Weighing the patient without a stretcher with built-in bed scales would require a Hoyer lift scale, and because tPA should be given as soon as possible, this could delay care. As a result, dosing errors could be frequent. These errors were documented by many across different patient populations.4,5 Bruer et al provide a useful account that details body weight estimation …

A phase II study of tasisulam sodium (LY573636) as second-line treatment for patients with unresectable or metastatic melanoma.

8541 Background: Tasisulam is a novel anticancer agent that induces apoptosis through the intrinsic pathway and has antiangiogenic properties in vitro. The mechanism of action is being further evaluated. Tasisulam has demonstrated activity across a broad range of tumors, including melanoma. The primary objective of this phase II study was to determine the overall response rate (ORR) in pts who received tasisulam as second-line chemotherapy for unresectable or metastatic melanoma. Secondary objectives aimed to characterize the clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), duration of response, and the pharmacokinetics and safety of tasisulam. Methods: Tasisulam was administered IV over 2 hours on day 1 of 21-day cycles using a lean body weight-based dosing algorithm targeting a Cmax of 420 μ g/mL as a loading dose in cycle 1 and a chronic dose (65% of the loading dose) in subsequent cycles. Tumor response (investigator assessed) was evaluated according to RECIST and toxicity according to NCI-CTC (v3). Results: Of the 68 pts enrolled, 26 (38%) were females and 42 (62%) were males with a median age of 59 years (range, 26-83). Most pts had an ECOG PS of 1 (54%) and stage IV disease (88%). No pts had CR; 8 (12%) pts had PR, for an ORR (CR+PR) of 12% (90% CI, 5-18%). 24 (35%) pts had SD (no progression after 2 cycles), and the CBR (CR+PR+SD) was 47% (90% CI, 37-57%); 25 (37%) pts had PD, and 11 (16%) pts did not have complete lesion measurements. Median PFS was 2.6 months (90% CI, 1.5-2.9) and median OS was 9.6 months (90% CI, 7.1-11.9). Most common (> 5 pts) grade 3 and 4 drug-related hematologic toxicities were thrombocytopenia in 3 (4%) and 11 (16%) pts, neutropenia in 5 (7%) and 6 (9%) pts, respectively, and anemia in 5 (7%) pts (grade 3 only). Most common drug-related nonhematologic toxicities were fatigue in 5 (7%) and mucositis/stomatitis in 3 (4%) pts (grade 3 only). Conclusions: Tasisulam administered at a targeted Cmax of 420 μ g/mL on day 1 of 21-day cycles demonstrated activity and tolerable toxicity as second-line treatment in pts with malignant melanoma. A registration trial is ongoing in metastatic melanoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly Eli Lilly Australia, Lilly Lilly Eli Lilly Australia Eli Lilly Australia, Lilly Eli Lilly Australia

Pegylated Interferons for the Treatment of Chronic Hepatitis C

Chronic infection with hepatitis C virus (HCV) is a major healthcare problem, affecting an estimated 170 million people worldwide. Interferon-alpha has formed the basis of treatment regimens since the identification of HCV, either alone or in conjunction with the nucleoside analogue ribavirin. The relatively recent introduction of pegylated forms of interferon-alpha, with greater stability and in vivo activity, has substantially improved sustained virological response (SVR) rates compared with unmodified interferon-alpha, with SVR rates of 35-66% when used in conjunction with ribavirin in randomized controlled trials. Two pegylated interferon (peginterferon)-alpha molecules are commercially available for the treatment of chronic hepatitis C, and these differ in the size and nature of the covalently attached polyethylene glycol (PEG) moiety, with resulting differences in pharmacokinetics and in dosing regimens. Peginterferon-alpha-2b has a linear 12 kDa PEG chain covalently attached primarily to histidine-34 of interferon-alpha-2b via an unstable urethane bond that is subject to hydrolysis once injected, releasing native interferon-alpha-2b. The branched, 40 kDa PEG chain of peginterferon-alpha-2a is covalently attached via stable amide bonds to lysine residues of interferon-alpha-2a, and circulates as an intact molecule. Consequently, peginterferon-alpha-2a has a very restricted volume of distribution, longer half-life and reduced clearance compared with native interferon-alpha-2a, and can be given once weekly independently of bodyweight. Peginterferon-alpha-2b has a shorter half-life in serum than peginterferon-alpha-2a and requires bodyweight-based dosing. The majority of head-to-head randomized controlled trials, including the large, randomized IDEAL (Individualized Dosing Efficacy versus Flat Dosing to Assess Optimal Pegylated Interferon Therapy) trial (n = 3070), demonstrated similar SVR rates for peginterferon-alpha-2a and peginterferon-alpha-2b (41% vs 39% in IDEAL), in combination with ribavirin; however, two randomized controlled trials (n = 431 and 320) demonstrated a statistically significant benefit for peginterferon-alpha-2a (66% vs 54%, and 69% vs 54%). Furthermore, two large retrospective studies and one prospective observational study in real-life settings have shown a significant benefit for peginterferon-alpha-2a versus peginterferon-alpha-2b, although SVR rates were generally lower than those seen in controlled trials. The use of interferon-alpha with or without ribavirin is frequently associated with a range of adverse effects, including influenza-like symptoms, haematological changes and neuropsychiatric disturbances, and this is true also of the peginterferons, with similar levels of adverse events, dose reduction and discontinuation from treatment. Peginterferon-alpha-2a and peginterferon-alpha-2b appear from comparative studies to be similarly tolerated, with few differences of clinical significance noted. Peginterferon plus ribavirin, as the standard of care for patients with chronic hepatitis C, may in the future form the basis of improved treatment regimens that include new, targeted anti-HCV agents to increase SVR rates even further.

Population pharmacokinetics of CP-751,871, a monoclonal antibody against IGF-I receptor, in patients with multiple myeloma or solid tumors

2524 Background: CP-751,871, a fully human IgG2 monoclonal antibody against the insulin-like growth factor type I receptor (IGF-IR), is currently under clinical development for cancer treatment. The aim of the present work was to develop a population model for characterizing the pharmacokinetics (PK) of CP-751,871 in cancer patients. Methods: CP-751,871 concentration-time data were obtained from 34 patients with multiple myeloma and 46 patients with solid tumors, who received escalating doses of CP-751,871 via intravenous infusions in the dose range of 0.1 to 20 mg/kg. Nonlinear mixed effects modeling was conducted using NONMEM to obtain the structural model describing CP-751,871 disposition and the statistic models describing intra- and inter-patient variabilities. Possible covariates contributing to inter-patient PK variability were also explored. Results: A mechanism-based structural PK model with a saturable elimination process best described the disposition of CP-751,871 in cancer patients. For variance models, inter-patient variability in PK disposition parameters was described by an exponential error model, and the residual variability was best described by a log-normal additive residual error model. Body weight was identified as a covariate for the initial distribution volume and the plasma clearance parameters. Age, sex, and albumin or bilirubin concentrations showed no apparent effects on CP-751,871 PK. In addition, there was no apparent difference in PK between multiple myeloma and solid tumor patients. Conclusions: A population PK model was developed to describe the concentration-time profiles of CP-751,871 in cancer patients. The identification of body weight as a significant covariate for plasma clearance validates the appropriateness of body weight-based dosing for CP-751,871. The population PK model can be applied to further explore pharmacokinetic/pharmacodynamic (PK/PD) relationships of CP-751,871 in cancer patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pfizer Oncology Pfizer Oncology Pfizer Oncology Pfizer Oncology

Growth Hormone Replacement Therapy in Adults with Growth Hormone Deficiency Improves Maximal Oxygen Consumption Independently of Dosing Regimen or Physical Activity

Several studies have demonstrated an improvement in aerobic exercise capacity with 6 months of GH replacement in adults with GH deficiency (GHD). The objective of the study was to determine whether improvements in aerobic exercise capacity with GH treatment in adults with GHD are related to changes in physical activity or affected by the GH dosing regimen. This was a randomized, two-arm, parallel, open-label study. The study was conducted at five academic medical centers with exercise physiology laboratories. Study subjects were adults (n = 29) with GHD due to hypothalamic-pituitary disease. The intervention was GH replacement therapy, administered either as a fixed body weight-based dosing regimen as an individualized dose titration regimen for 32 wk. Maximal oxygen consumption (VO2 max) and oxygen consumption (VO2) at the lactate threshold, ventilatory threshold using a cycle ergometry protocol, and weekly energy expenditure (physical activity questionnaire), assessed at baseline and end point, were measured. In the group as a whole, VO2 max increased significantly (by 9%) from baseline (19.1+/- 0.89 ml/kg.min) to end point (21.6 +/- 1.23 ml/kg.min, P = 0.010). Compared with baseline, VO2 max also changed significantly within the individualized dose titration regimen group (+2.5 +/- 0.98 ml/kg.min, P =0.034) but not within the fixed body weight-based dosing regimen group (+1.2 +/- 0.78 ml/kg.min, P = 0.15), although these changes from baseline were not significantly different between the two groups. VO2 at lactate threshold, VO2 at ventilatory threshold, and weekly energy expenditure also did not change. GH replacement therapy in GH-deficient adults improved VO2 max similarly with both dosing regimens, without any influence of physical activity. There was no effect on submaximal exercise performance.

Population Pharmacokinetics of Enfuvirtide in HIV‐1‐Infected Pediatric Patients Over 48 Weeks of Treatment

The objective of this study was to characterize the population pharmacokinetics of enfuvirtide in HIV-1-infected children and adolescents. HIV-infected patients received combination antiretroviral therapy, including enfuvirtide 2.0 mg/kg subcutaneously, twice daily. Serial and trough blood samples were collected up to 48 weeks. NONMEM was used for population pharmacokinetic analysis. Enfuvirtide exposure was calculated from individual parameter estimates derived from the final model. A total of 218 samples from 43 patients were included in the analysis. Enfuvirtide plasma concentration-time data were described by a 1-compartment model with first-order absorption and elimination. The addition of each subject's actual body weight as a covariate affected CL/F but not V/F or K(a). The population CL/F, V/F, and K(a) for a 33-kg reference patient was 1.31 L/h, 2.31 L, and 0.105 h(-1), respectively. The final model was CL/F (L/h) = 1.31 . (body weight/33 [kg])(0.721). Age did not affect enfuvirtide exposure. These results confirm the appropriateness of body weight-based pediatric enfuvirtide dosing.

Intravenous Busulfan

An intravenous formulation of busulfan, a cytotoxic bifunctional alkylating agent, has been developed to replace oral busulfan as a conditioning treatment prior to hematopoietic stem cell transplantation (HSCT) in pediatric patients. Doses of intravenous busulfan based on actual bodyweight, but not age, reduce inter- and intraindividual variability in exposure. In a study of intravenous busulfan as a conditioning treatment prior to allogeneic or autologous HSCT, the majority of pediatric patients, who received one of five bodyweight-based doses, achieved busulfan area under the plasma concentration-time curve (AUC) values within the targeted therapeutic range. Although mean busulfan clearance values were highly variable between bodyweight strata, exposure was not affected, with no significant differences between bodyweight groups in mean AUC values. The achievement of therapeutic AUC values with intravenous busulfan resulted in a high rate of sustained engraftment, low transplant-related mortality, and promising survival outcomes post-transplant. Intravenous busulfan was considered to be well tolerated, in the particular context of HSCT, and no failure of HSCT due to organ toxicity was reported. Nonhematologic adverse events commonly associated with busulfan conditioning regimens were frequent, but generally of mild to moderate severity. The intravenous busulfan regimen was frequently associated with elevated liver enzymes, but hepatic veno-occlusive disease (HVOD) was infrequent, of mild to moderate severity, and resolved within 10 days of diagnosis. Unlike oral busulfan, intravenous busulfan does not appear to be associated with severe HVOD or death due to organ toxicity.

Rationale for fixed dosing of pertuzumab by population pharmacokinetic (POP PK) modeling

Background Pertuzumab (rhuMAb 2C4), a humanized IgG1 monoclonal antibody, is a novel HER2 dimerization inhibitor (HDI) being evaluated in the clinic for a variety of solid tumors. Objective To develop a POP PK model for pertuzumab, evaluate predictive covariates, and examine the variability of steady-state trough concentrations after fixed (FBD), or body weight-based dosing (WBD). Methods Pertuzumab was administered by IV infusion (q3 week) either as a weight-based dose (0.5–15 mg/kg) or a fixed dose (420 mg or 1050 mg). PK data from one Phase Ia and two Phase II trials (Ovarian and Breast), comprising of 153 patients and 1458 concentration-time points, were pooled for this analysis using NONMEM with the FOCE interaction method. Patient weights ranged from 45.0–150.6 kg. Results A linear 2-compartment model best described the data. Body weight, serum albumin, and alkaline phosphatase were significant covariates affecting clearance (CL). Weight only explained 8.3% of inter-patient variability for CL. Evaluation of the final POP PK model using a posterior predictive check showed good performance. Simulations showed that the percentages of predicted steady-state trough concentrations below 20 mcg/mL were similar between FBD and WBD, with WBD reducing the population variability by only 6.2%. Conclusion Although humanized antibodies are typically dosed by weight, our analyses demonstrate the feasibility of administrating pertuzumab using a fixed dose in patients with ovarian and breast cancers. Clinical Pharmacology & Therapeutics (2005) 77, P33–P33; doi: 10.1016/j.clpt.2004.12.019

Infant exposure to dioxin-like compounds in breast milk.

We used a one-compartment, first-order pharmacokinetic model to predict the infant body burden of dioxin-like compounds that results from breast-feeding. Validation testing of the model showed a good match between predictions and measurements of dioxin toxic equivalents (TEQs) in breast-fed infants, and the exercise highlighted the importance of the assumption of the rate of dissipation of TEQs in the infant. We evaluated five nursing scenarios: no nursing (i.e., formula only), and nursing for 6 weeks, 6 months, 1 year, and 2 years. We assumed that an infant weighs 3.3 kg at birth and is exposed to a total of 800 pg TEQ/day by consumption of breast milk, leading to an estimated body weight-based dose of 242 pg TEQ/kg-day, which drops to 18 pg TEQ/kg-day after 1 year. This decline is due to declines in dioxin concentration in mother's milk and infant body weight increases. This range is significantly higher, on a body-weight basis, than adult TEQ exposure, which has been estimated to average about 1 pg TEQ/kg-day. For the nursing scenarios of >or= 6 months, we predict that body burdens (expressed as a body lipid concentration) peak at around 9 weeks at 44 ppt TEQ lipid. We predict that the body burden of the formula-fed infants will remain below 10 ppt TEQ lipid during the first year. These results compare to the current adult average body burden of 25 ppt TEQ lipid. We also found that an infant who had been breast-fed for 1 year had an accumulated dose 6 times higher than a 1-year-old infant who had not been breast-fed. For a 70-year lifetime, individuals who had been breast-fed had an accumulated dose 3-18% higher than individuals who had not been breast-fed.