Model-Based Phase 3 Dose Selection for HIV-1 Attachment Inhibitor Prodrug BMS-663068 in HIV-1-Infected Patients: Population Pharmacokinetics/Pharmacodynamics of the Active Moiety, BMS-626529.

BMS-663068 is an oral prodrug of the HIV-1 attachment inhibitor BMS-626529, which prevents viral attachment to host CD4(+) T cells by binding to HIV-1 gp120. To guide dose selection for the phase 3 program, pharmacokinetic/pharmacodynamic modeling was performed using data from two phase 2 studies with HIV-1-infected subjects (n = 244). BMS-626529 population pharmacokinetics were described by a two-compartment model with first-order elimination from the central compartment, zero-order release of prodrug from the extended-release formulation into a hypothetical absorption compartment, and first-order absorption into the central compartment. The covariates of BMS-663068 formulation type, lean body mass, baseline CD8(+) T-cell percentage, and ritonavir coadministration were found to be significant contributors to intersubject variability. Exposure-response analyses showed a relationship between the loge-transformed concentration at the end of a dosing interval (Ctau) normalized for the protein binding-adjusted BMS-626529 half-maximal (50%) inhibitory concentration (PBAIC50) and the change in the HIV-1 RNA level from the baseline level after 7 days of BMS-663068 monotherapy. The probability of achieving a decline in HIV-1 RNA level of >0.5 or >1.0 log10 copies/ml as a function of the loge-transformed PBAIC50-adjusted Ctau after 7 days of monotherapy was 99 to 100% and 57 to 73%, respectively, for proposed BMS-663068 doses of 400 mg twice daily (BID), 600 mg BID (not studied in the phase 2b study), 800 mg BID, 600 mg once daily (QD), and 1,200 mg QD. On the basis of a slight advantage in efficacy of BID dosing over QD dosing, similar responses for the 600- and 800-mg BID doses, and prior clinical observations, BMS-663068 at 600 mg BID was predicted to have the optimal benefit-risk profile and selected for further clinical investigation. (The phase 2a proof-of-concept study AI438006 and the phase 2b study AI438011 are registered at ClinicalTrials.gov under numbers NCT01009814 and NCT01384734, respectively.).

Population pharmacokinetics of atacicept in systemic lupus erythematosus: An analysis of three clinical trials.

B cell stimulating factor (BLyS) and a proliferation-inducing ligand (APRIL) are targets for novel treatments in patients with systemic lupus erythematosus (SLE). Atacicept is a recombinant, soluble fusion protein that blocks BLyS and APRIL activity. This study characterized the pharmacokinetic (PK) profile of atacicept using a population PK model and identified covariates explaining the PK variability. Total atacicept concentrations from a phase I study in healthy volunteers and two phase II studies in patients with SLE, using subcutaneous administration, were modeled using a quasi-steady-state approximation of the target-mediated drug disposition model with first-order absorption. The model included 3640 serum atacicept concentration records from 37 healthy volunteers and 503 patients with SLE and described total atacicept concentrations of the three trials, providing precise estimates of all parameters. Body weight and baseline BLyS concentration were the only statistically significant covariates, whereas no differences were found between patients and healthy volunteers. Apparent clearance and volume of the central compartment increased with body weight and initial target concentration increased with baseline BLyS. The change on atacicept exposure was moderate, with a difference in area under the curve compared with the median of 20%-32% for body weight, and 7%-18% for BLyS. Therefore, the effects of these covariates on atacicept exposure are not expected to be clinically relevant. The model described the complete total atacicept concentration-time profiles without finding any differences between healthy subjects and patients with SLE and supports the 150 mg once weekly dose for further trials.

Oliceridine (TRV130), a Novel G Protein-Biased Ligand at the µ-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model.

Conventional opioids bind to µ-opioid receptors and activate 2 downstream signaling pathways: G-protein coupling, linked to analgesia, and ß-arrestin recruitment, linked to opioid-related adverse effects and limiting efficacy. Oliceridine (TRV130) is a novel G protein-biased ligand at the µ-opioid receptor that differentially activates G-protein coupling while mitigating ß-arrestin recruitment. Using data derived from both phase 1 studies in healthy volunteers as well as data from a phase 2 study examining the efficacy of oliceridine for the treatment of postbunionectomy pain, we have developed a population pharmacokinetic/pharmacodynamic model linking the pharmacokinetics of oliceridine to its effect on pain, as measured by the Numeric Pain Rating Scale score. Phase 1 data consisted of 145 subjects (88% male, 12% female), who received single doses of oliceridine ranging between 0.15 and 7 mg, as well as multiple doses ranging from 0.4 to 4.5 mg every 4-6 hours. Sixteen of these subjects were CYP2D6 poor metabolizers, who have lower oliceridine clearance than extensive metabolizers. Approximately 265 subjects (10% male, 90% female) came from the phase 2 study, in which they received active doses ranging from 0.5 to 4 mg every 3-4 hours. The final model was a 3-compartment model that included covariates of body weight, sex, and CYP2D6 status. The PD model was an indirect response model linked to plasma oliceridine concentrations and included the placebo pain response over the 48-hour treatment period. The EC50 for oliceridine on pain relief was estimated as 10.1 ng/mL (95%CI, 8.4-12.1 ng/mL). Model qualification showed that the model robustly reproduced the original data.

Oliceridine, a Novel G Protein-Biased Ligand at the µ-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. II: Simulation of Potential Phase 3 Study Designs Using a Pharmacokinetic/Pharmacodynamic Model.

Oliceridine is a novel G protein-biased ligand at the µ-opioid receptor that differentially activates G protein coupling while mitigating ß-arrestin recruitment. Unlike morphine, oliceridine has no known active metabolites; therefore, analgesic efficacy is predictably linked to its concentration in the plasma. Oliceridine is primarily hepatically metabolized by CYP3A4 and CYP2D6. Using a pharmacokinetic/pharmacodynamic model relating oliceridine plasma concentrations to its effect on pain intensity as measured by numeric pain-rating scale (NPRS) scores, we have simulated potential dosing regimens using both fixed-dose regimens and as-needed (prn) dosing regimens in which various doses of oliceridine were administered if NPRS scores indicated moderate to severe pain (≥4 on a 0-10 scale). In addition, regimens in which oliceridine was self-administered via a patient-controlled analgesia device were also simulated. The simulated population included 10% CYP2D6 poor metabolizers (PM). The simulation results suggest that oliceridine doses of 1-3 mg prn should be effective in reducing NPRS scores relative to placebo. The simulations also revealed that a 1-mg "supplemental dose" given 0.25 hour after the loading dose would decrease NPRS scores further in almost one-third of patients. In addition, if oliceridine is administered prn, a longer interval between doses is observed in simulated PM patients, consistent with their reduced oliceridine clearance. Because this longer average dosing interval is predicted to decrease oliceridine exposure in PM patients, the need to know the patient's CYP2D6 genotype for dosing is effectively obviated.

Retrospective population pharmacokinetics of levocetirizine in atopic children receiving cetirizine: the ETAC study.

AIMS: To evaluate the population pharmacokinetics of levocetirizine in young children receiving long-term treatment with cetirizine. METHODS: Data were available from a randomized, double-blind, parallel group and placebo-controlled study of cetirizine in 343 young children between 12 and 24 months of age at entry, who were at high risk of developing asthma, but were not yet affected (ETAC study). Infants received oral drops of cetirizine at 0.25 mg kg(-1) twice daily for 18 months. Plasma concentration of the active enantiomer levocetirizine was determined in blood samples collected at months 3, 12 and 18 (1-3 samples per child). A one-compartment open model was fitted to the data using nonlinear mixed effects modelling (NONMEM). The influence of weight, age, gender, BSA and other covariates on CL/F and V/F was evaluated. RESULTS: CL/F increased linearly with weight by 0.044 l h(-1) kg(-1) over an intercept of 0.244 l h(-1), and V/F increased linearly with weight by 0.639 l kg(-1). Population estimates in children with weights of 8 and 20 kg were 0.60 and 1.13 l h(-1) for CL/F, and 5.1 and 12.8 l for V/F, respectively, with interpatient variabilities of 24.4% and 14.7%. Weight-normalized estimates of CL/F and V/F were higher than in adults. The estimated relative bioavailability was 0.28 in 12% of instances of suspected noncompliance. Levocetirizine pharmacokinetics were not influenced by severe allergy or aeroallergen sensitization. Results on the effects of concomitant medications or diseases were inconclusive due to limited positive cases. AUC(ss), calculated in compliant subjects using posterior estimates of the final model, was 1952 (1227-3319) microg l(-1) h (mean, min-max), a value similar to that in adults after intake of 5 mg oral solution (2036 (1414-2827) microg l(-1) h. CONCLUSIONS: The model suggests that administration of levocetirizine 0.125 mg kg(-1) twice daily in children 12-48 months of age or weighing 8-20 kg yields the same exposure as in adults taking the recommended dose of 5 mg once daily.

A Bayesian method based on clotting factor activity for the prediction of maintenance warfarin dosage regimens.

A Bayesian algorithm, employing a population pharmacokinetic-pharmacodynamic model, for the effective and rapid prediction of warfarin maintenance dosing requirements was developed. The algorithm was evaluated prospectively in five healthy volunteers who were given a 15-mg single dose of racemic warfarin. Based on previous population pharmacokinetic and pharmacodynamic parameters and factor VII response measurements taken during the first 48 hours, dosage regimens to achieve a subtherapeutic degree of anticoagulation (50% of normal) were determined. Three factor VII response measurements were sufficient to determine dosing requirements in the five volunteers. The advantage of the algorithm is that it does not require warfarin concentration measurements and uses non-steady-state data.

Modeling nicotine arterial-venous differences to predict arterial concentrations and input based on venous measurements: application to smokeless tobacco and nicotine gum.

Significant arterio-venous differences in nicotine concentrations have been observed during and after cigarette smoking, nicotine nasal spray, and intravenous nicotine administration. In this paper we describe a novel mathematical method for estimating arterial blood levels from venous blood level data. The model allows to quantify: (i) the influence of the microcirculation in the hands and forearm on the distribution of nicotine, and (ii) the influence of disregarding the venous to arterial circulation in the estimate of systemic inputs. We also (iii) propose a general method to predict arterial concentrations and inputs given venous data. The basic model we adopt is based on the relationship Cv = T * Ca, where Cv and Ca are the concentration in the venous and arterial site, respectively, T is the arterio-venous transfer function and * indicates convolution. We use empirical data to estimate T. We then compare estimates of systemic inputs to the venous site obtained taking into account the transfer function or, as usually done, disregarding it. The relationship we use to compare estimated inputs are: Cv = T * ka * A (where Ka is the arterial disposition function and A the systemic input), and Cv = Kv * A (where Kv is the venous disposition function), respectively. Finally, the estimated transfer function allows to estimate (average) Ca or A given arbitrary venous data. (i) Our analysis suggests that a bi-exponential T is needed to describe observed arterial-venous differences. The estimated transfer function indicates that no elimination of nicotine is involved in the forearm. (ii) Disregarding T, as usually done, erroneously obtains too complex venous input functions (because these input functions incorporate T). (iii) Disregarding T erroneously estimates significantly higher total inputs. (iv) Using the proposed model and previously published venous nicotine level data we predict substantial arterial-venous differences in blood nicotine levels for smokeless tobacco and nicotine gum. The use of disposition functions obtained from venous data may lead to erroneous estimation of the rates of entry into the circulation and systemic bioavailability for many drugs.

Retrospective population pharmacokinetic analysis of cetirizine in children aged 6 months to 12 years.

AIMS: To evaluate retrospectively the population pharmacokinetics of cetirizine, a second-generation antihistamine, in children. METHODS: Data were pooled from six clinical trials, in which cetirizine was administered orally in various formulations and in single and multiple dosage regimens. The population consisted of 112 children (33 female and 79 male) aged 6 months to 12 years. A one-compartment open model with first-order absorption and elimination was fitted to the plasma concentration-time profiles using nonlinear mixed effects modelling with first-order estimation. RESULTS: A linear association was found between apparent clearance (CL/F) and age with the former increasing by 0.12 l h(-1) per year. The intercept of the relationship was slightly lower for female children (0.59 vs. 0.77 l h(-1) in male). The population estimate of CL/F for an average age of 7 years was 1.61 and 1.43 l h(-1) for male and female children, respectively. A linear association was found between apparent volume of distribution (V/F) and age with the former increasing by 1.4 l year(-1), with an intercept of 4.0 l. The population estimate of V/F for an average age of 7 years was 13.9 l. The magnitudes of interpatient variability were 35.6% for CL/F and 19.7% for V/F. The magnitude of residual variability in cetirizine concentrations was 26.9%. CONCLUSIONS: Population analysis predicts a linear increase in cetirizine CL/F and V/F with age, with CL/F being slightly lower in female children, relative to males of the same age. However, this gender difference probably has no clinical consequences. Since V/F increased more rapidly with age than CL/F, a nonlinear increase in half-life was seen, from < 4 h in infants to near the adult value at 12 years of age. The current recommended dosing regimens that younger children should receive lower but more frequent doses, are confirmed by the present analysis.

Influence of arterial vs. venous sampling site on nicotine tolerance model selection and parameter estimation.

In this modeling study we utilize previously published nicotine pharmacokinetic (PK) and pharmacodynamic (PD, heart rate) data to investigate the influence of PK sampling site (venous vs. arterial) on the selection of a specific PD tolerance model and estimation of its parameters. We describe a general model for tolerance which includes as special cases feedback (TF), and kinetic based tolerance (TK) models. A TK model has arterial plasma drug concentrations (Ca) driving (hypothetical) effect (Ce) and antagonist (Cm) site concentrations, which drive a non-feedback effect (Enf): tolerance depends on the relative rate of equilibration of Ce and Cm with Ca. The TF model adds feedback which makes tolerance depend on Enf, not just on drug kinetics for nicotine. The arterial-sampling-analysis (PKPDa) has Ca driving Ce and Cm. The venous-sampling-analysis (PKPDv) does the same but estimates Ca from venous data by means of deconvolution. A TF model (with Cm = Ce) was always selected in the PKPDa. According to this model tolerance developed rapidly with a median half-life of 6.6 min, and median decrease of effect due to tolerance of 31%. Different variants of the TF or TK models were selected in the PKPDv. Parameter estimates for PKPDv show higher variability, and, for the TF model, lower rate and extent of tolerance development and threefold increase in EC50. The study shows that (i) TF models are more appropriate than TK models to describe nicotine effect data, (ii) venous sampling may lead to incorrect model selection and inaccurate and imprecise parameter estimation in respect to arterial sampling, and (iii) arterial sampling should be preferred for accurate (non-steady-state) PD modeling.