Population pharmacokinetic and covariate analyses of intravenous trastuzumab (Herceptin®), a HER2-targeted monoclonal antibody, in patients with a variety of solid tumors.

PURPOSE: The aim of the study was to characterize the population pharmacokinetics (PK) of the intravenous formulation of trastuzumab, assess the impact of patient and pathological covariates on trastuzumab PK, and perform simulations to support dosing recommendations in special situations. METHODS: Serum trastuzumab concentrations were obtained from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC), or other tumor types/healthy volunteers in 18 phase I, II, and III trials and analyzed by nonlinear mixed-effects modeling. RESULTS: A two-compartment model with parallel linear and nonlinear elimination best described the data. During treatment, linear clearance (CL) dominated, resulting in a total CL of 0.173-0.337 L/day, which is similar to other IgG1 monoclonal antibodies. Covariates influencing CL were baseline body weight, aspartate aminotransferase, albumin, gastric cancer, and the presence of liver metastases. MBC and EBC had similar PK parameters, while CL was higher in AGC. Simulations indicated that at least 95% of patients with BC reach concentrations < 1 µg/mL (~ 97% washout) by 7 months. A dose delay in BC or AGC patients of > 1 week would take approximately 6 weeks to get back within steady-state exposure range. CONCLUSIONS: Trastuzumab PK for the intravenous formulation was well-described across cancer types, disease status, and regimens. No dose adjustment is required for any of the identified patient covariates. A 7-month serum washout period for trastuzumab is recommended. A reloading dose is required if a maintenance dose is missed by > 1 week.

Pharmacokinetic Properties of a Sufentanil Sublingual Tablet Intended to Treat Acute Pain.

BACKGROUND: Desirable product attributes for treatment of moderate-to-severe acute pain in many medically supervised settings are rapid onset and a route of administration not requiring intravenous access. The pharmacokinetic characteristics of sublingually administered tablets containing 15 or 30 µg of sufentanil are described. METHODS: Blood was sampled from healthy subjects (four studies, 122 subjects) and patients (seven studies, 944 patients). Studies in healthy subjects determined bioavailability, effect of inhibition of cytochrome P450 3A4, and the plasma concentration profile with single and hourly sublingual doses. Studies in patients evaluated effects of weight, age, sex, and organ impairment on apparent clearance. Noncompartmental and mixed-effect population methods were used. RESULTS: Bioavailability of a single sublingual tablet was 52%, decreasing to 35% with repeat dosing. Ketoconazole (CYP3A4 inhibitor) increased maximum plasma concentration 19% and increased the area under the curve 77%. After a single 30-µg dose, plasma concentrations reached the published sufentanil analgesic threshold (24 pg/ml) within 30 min, peaked at 1 h, and then decreased below therapeutic concentrations by ~3 h. With hourly administration, plasma concentrations plateaued by the fifth dose. Time for concentrations to decrease 50% from maximal values was similar after 1 dose (2.5 ± 0.85 h) and 12 doses (2.5 ± 0.72 h). Clearance increased with weight, decreased with age, and was not affected by renal or hepatic impairment. CONCLUSIONS: The time course of a single 30-µg dose was consistent with onset of analgesia and redosing frequency observed in clinical trials. Sublingual sufentanil tablets provide the opportunity to noninvasively and rapidly treat moderate-to-severe pain in a monitored setting.

Pharmacokinetic and exposure-response analyses of pertuzumab in combination with trastuzumab and docetaxel during neoadjuvant treatment of HER2+ early breast cancer.

PURPOSE: The NeoSphere trial evaluated pertuzumab in the neoadjuvant setting [early breast cancer (EBC)] with pathological complete response (pCR) as the primary efficacy end point. This analysis of pertuzumab aimed to (1) compare its pharmacokinetics (PK) in patients with EBC versus advanced cancers, (2) to further evaluate PK drug-drug interactions (DDIs) when given in combination with trastuzumab, and (3) to assess the relationship between exposure and efficacy to assess the clinical dosing regimen in the EBC patients. METHODS: Pertuzumab serum concentration data from 180 patients in NeoSphere were compared to historical observations and potential DDI was assessed, by applying simulation techniques using a population PK model. The impact of pertuzumab exposure on pCR rate was evaluated using a logit response model (n = 88). RESULTS: The observed PK matched the population PK model simulations, confirming that the PK in neoadjuvant EBC appear to be in agreement with the historical observations. No evidence of a DDI effect of trastuzumab or docetaxel on pertuzumab was observed supporting the doses when given in combination. In NeoSphere >90% of EBC patients achieved the non-clinical target serum concentration. There was no association between the pertuzumab serum concentration and pCR within the range observed in this study (20-100 µg/mL) supporting no dose adjustments needed for patients with lower exposure. CONCLUSIONS: This analysis further supports the lack of DDI between the two therapeutic proteins and the appropriateness of the approved fixed non-body-weight-adjusted pertuzumab dose in the treatment of neoadjuvant EBC with pertuzumab in combination with trastuzumab and docetaxel.

Modeling and Simulation to Support Phase 2 Dose Selection for RG7652, a Fully Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9.

RG7652 is a fully humanized monoclonal antibody targeting human PCSK9, a regulator of serum low density lipoprotein cholesterol (LDLc) levels. RG7652 prevents degradation of the hepatic LDLc receptors by blocking PCSK9 binding and thereby resulting in efficient LDLc uptake by hepatocytes. The pharmacokinetics of RG7652 have been evaluated in healthy subjects after single and multiple subcutaneous doses. Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to explain the antibody PK and LDLc time course data. The PK and PD models based on data from healthy subjects were used to simulate the effects of RG7652 on LDLc levels for a range of potential dose regimens in patients with coronary heart disease. A one-compartment PK model combined with an indirect PD response model was able to adequately describe the PK and LDLc data. Simulations of 400 mg every 4 weeks or 800 mg every 8 weeks regimens show significant LDLc reduction and suggest that dosing RG7652 once every month or once every 2 months is predicted to be optimal for the treatment of hypercholesterolemia. The PK and PD model successfully described the PK and LDLc data from healthy subjects in a Phase 1 study, and the model-based simulations provided useful insights and quantitative understanding for the selection of Phase 2 study doses in patients with coronary heart disease. The approach used in the case study demonstrates the utility of modeling and simulation in designing dose-ranging studies.

Population pharmacokinetic and covariate analysis of pertuzumab, a HER2-targeted monoclonal antibody, and evaluation of a fixed, non-weight-based dose in patients with a variety of solid tumors.

PURPOSE: To characterize the population pharmacokinetics (PK) of pertuzumab across clinical trials in a variety of solid tumors, evaluate the potential impact of patient characteristics on PK, and confirm the appropriateness of the fixed (non-weight-based) dose. METHODS: Pertuzumab concentration data collected following intravenous administration during eleven phase I/II studies and the pivotal phase III trial CLEOPATRA were analyzed using nonlinear mixed-effects modeling. The potential impact of patient and laboratory characteristics and HER2 target-related variables on pertuzumab PK were investigated in a covariate analysis. The final model was used to confirm selection of fixed, non-weight-based dosing of pertuzumab, and to compare pertuzumab PK in CLEOPATRA with the other studies. RESULTS: The analysis included 4,525 serum concentration measurements from 481 patients with solid tumors. Pertuzumab PK in the 2-25 mg/kg dose range was described by a two-compartment linear model with first-order elimination. The elimination clearance and central compartment volume were 0.235 L/day, and 3.11 L, respectively, and the terminal elimination half-life was 18.0 days. Baseline serum albumin and lean body weight had statistically significant effects on pertuzumab clearance; however, simulations showed that the magnitude of their effects on pertuzumab exposure was minimal compared with overall variability and was not clinically relevant. Thus, variations in these factors do not require dose adjustments. CONCLUSIONS: The fixed, non-weight-based dosing of pertuzumab, 840 mg loading dose followed by a 420 mg maintenance dose every 3 weeks, in patients with the solid tumors in this analysis is well supported by the population pharmacokinetic modeling and simulation results.

Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis.

OBJECTIVE: To compare placebo responses in neuropathic pain syndromes. DESIGN: Systematic literature review and meta-analysis. SETTING AND PATIENTS: Randomized placebo-controlled trials assessing pain intensity or pain relief in any neuropathic pain syndrome published since 1995 with ≥5days follow-up. INTERVENTIONS: Placebo response. OUTCOME MEASURES: Pain intensity and responder rates (proportion reporting ≥50% pain relief). Meta-regression models were built. RESULTS: Ninety-four studies (N=5,317) were included in the pain intensity analysis; 47 studies (N=3,087) were included in the responder analysis. After controlling for potential confounders (e.g., subject characteristics, study design characteristics), the placebo response was found to be large and varied with the pain syndrome. Compared with diabetic neuropathic/polyneuropathic pain (DPN), the placebo response for a decline in pain intensity and responder rate was smaller in trials that assessed central pain and postherpetic neuralgia (PHN) and larger in trials that assessed HIV pain. The model-predicted mean decrease (95% confidence interval [CI]) from baseline in pain intensity (0-10 scale) was as follows: DPN, 1.45 (1.35 to 1.55); PHN, 1.16 (1.03 to 1.29); central pain, 0.44 (-0.41 to 1.30); HIV pain, 1.82 (1.51 to 2.12). The predicted responder rates (95% CI) were as follows: DPN, 20% (14.6 to 25.8); PHN, 11.5% (8.4 to 14.5); central pain, 7.2% (2.1 to 12.3); HIV pain, 42.8% (34.9 to 50.7). The type of treatment in the active arm also influenced the placebo response. CONCLUSIONS: Placebo response is influenced by the pain syndrome evaluated. These differences should be considered when evaluating novel compounds for the treatment of neuropathic pain conditions.

Enriched analgesic efficacy studies: an assessment by clinical trial simulation.

BACKGROUND AND OBJECTIVE: Enrichment strategies which select subjects who appear to respond to the drug have been used in drug studies to demonstrate clinical efficacy. We have used clinical trial simulation techniques to examine factors that are relevant in clinical trial design based on enrichment where poor responders are excluded from the double-blind phase of the study. METHODS: Simulations were performed for an analgesic trial design involving an open-dose titration phase (enrichment phase) followed by a double-blind, randomized, placebo-controlled maintenance phase. Enrichment was examined by excluding subjects above a predefined pain score (cutoff) from analysis of efficacy for the maintenance phase. Cutoff pain scores ranging from 4 to 7 on a 0 to 10 categorical scale were examined. A database consisting of chronic pain patients who participated in studies with a new formulation of buprenorphine was used to build the simulation model. Since no data were available for the key model variable "correlation between treatment and placebo response", values of 0.25, 0.5, and 0.75 were used for the simulations. RESULTS: A correlation between treatment and placebo effect ranging from 0.75 to 0.25 will cause the likelihood of trial success to vary from 50% to 95%. This model also shows that recruitment efficiency will decrease with the use of lower cutoff pain scores. CONCLUSION: Prior to using enrichment techniques, investigators must consider the correlation between treatment effect and placebo response to optimize clinical trial design.

Population pharmacokinetics of olmesartan following oral administration of its prodrug, olmesartan medoxomil: in healthy volunteers and hypertensive patients.

BACKGROUND: Olmesartan medoxomil (CS-866) is a new orally active angiotensin II receptor antagonist that is highly selective for the AT1 receptor subtype. OBJECTIVE: To develop a population pharmacokinetic model for olmesartan (RNH-6270), the active metabolite of olmesartan medoxomil, in healthy volunteers and hypertensive patients, and to evaluate effects of covariates on the apparent oral clearance (CL/F), with particular emphasis on the effect of race. DESIGN: Retrospective analysis of data from 12 phase I-III trials in the US, Europe and Japan. PARTICIPANTS: Eighty-nine healthy volunteers and 383 hypertensive patients. METHODS: Nonlinear mixed-effects modelling was used to evaluate 7911 olmesartan plasma sample concentrations. The covariates included age, bodyweight, sex, race (Westerners [including Caucasians and Hispanics] versus Japanese), patient status (hypertensive patients versus healthy volunteers), serum creatinine level as an index of renal function and serum chemistry data as indices of hepatic function. RESULTS: The pharmacokinetic data of olmesartan were well described by a two-compartment linear model with first-order absorption and an absorption lag-time, parameterised in terms of CL/F (6.66 L/h for a typical male Western hypertensive patient), absorption rate constant (1.46h-1), elimination rate constant (0.193h-1), rate constant from the central to peripheral compartment (0.061h-1), rate constant from the peripheral to central compartment (0.079h-1) and absorption lag-time (0.427h). Analysis of covariates showed that age, bodyweight, sex, patient status and renal function were factors influencing the clearance of olmesartan. CONCLUSION: The population pharmacokinetic analysis of olmesartan showed that: (i) severe renal impairment (serum creatinine >265 micromol/L [approximately 3 mg/dL]) could cause a clearance decrease of > or =30%; (ii) older age, lower bodyweight and being female were determinants of lower clearance but their effects on olmesartan clearance were within 20%; (iii) no statistically significant difference in clearance was found between Westerners and Japanese.