Population pharmacokinetics and exposure-response of trilaciclib in extensive-stage small cell lung cancer and triple-negative breast cancer.

AIMS: Trilaciclib is a first-in-class, intravenous cyclin-dependent kinase 4/6 inhibitor that provides multilineage protection from chemotherapy-induced myelosuppression. This analysis aimed to characterize the population pharmacokinetics (PK) of trilaciclib, identify potential covariates influencing trilaciclib PK, and evaluate exposure-response relationships in extensive-stage small cell lung cancer (ES-SCLC) and triple-negative breast cancer (TNBC) trials. METHODS: Population PK analysis was performed using data from healthy volunteers (n = 72), patients with ES-SCLC (n = 111) and patients with TNBC (n = 14). Exposure-response analyses were conducted to investigate the impact of trilaciclib exposure (AUC) on myeloprotective efficacy, antitumour efficacy and safety. Logistic regression and Cox regression models were used for binary and time-to-event endpoints, respectively. RESULTS: Trilaciclib PK was described by a three-compartment model. Sex, body surface area, baseline albumin concentration and age were identified as significant covariates on trilaciclib PK but did not have clinically relevant impact on exposure. Based on exposure-response analyses, lower and higher exposures of trilaciclib at clinical doses (200-280 mg/m2 ) were associated with similar myeloprotective effects. Trilaciclib exposure did not impact the antitumour effects of chemotherapy. Higher exposure to trilaciclib was associated with higher probabilities of headache, phlebitis/thrombophlebitis and injection site reactions. CONCLUSION: No dose adjustments are required based on the covariates tested. Trilaciclib resulted in optimal myeloprotective effects with no impact on antitumour effects of chemotherapy. However, higher exposure increased the probabilities of adverse events. The data further support selection of the recommended phase 2 dose (trilaciclib 240 mg/m2 ).

Population pharmacokinetics and exposure-response analyses of teduglutide in adult and pediatric patients with short bowel syndrome.

Teduglutide is a recombinant analog of human glucagon-like peptide-2 that regulates the functional and structural integrity of the cells lining the gastrointestinal tract. Teduglutide is approved for the treatment of patients with short bowel syndrome (SBS) who are dependent on parenteral support (PS). Population pharmacokinetic (PK) and exposure-response analyses were performed to support teduglutide dosing in patients with SBS. The analysis included 219 patients with SBS (aged <1 year, 5 patients; 1-11 years, 86 patients; 12-17 years, 8 patients; 18-79 years, 120 patients), and 259 non-SBS subjects (including healthy volunteers and subjects with renal or liver impairment). A one-compartment model with first-order absorption and linear elimination adequately characterized the PKs of teduglutide. In patients with SBS, the apparent clearance (CL/F), volume of distribution (V/F), and elimination half-life of teduglutide were 16.0 L/h, 33.9 L, and 1.47 h, respectively. CL/F depended on body weight and renal function, and V/F depended on body weight and age. Maximum concentration (Cmax ) of teduglutide was similar in adult and pediatric patients, and in Japanese and non-Japanese patients. A time- and exposure-response model dependent on the Cmax of teduglutide adequately characterized the reduction in PS over more than 2 years of treatment. Daily dosing of 0.05 mg/kg teduglutide resulted in a maximum reduction in PS of 5.76 L/week. Higher Cmax values were associated with a more important reduction in PS over time. Adult and pediatric patients with SBS presented similar PKs and response to teduglutide.

Pharmacokinetics, Pharmacodynamics, and Exposure-Response of Lanadelumab for Hereditary Angioedema.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disorder characterized by unpredictable, potentially life-threatening recurrent angioedema attacks. Lanadelumab is a fully human monoclonal antibody with selective binding to active plasma kallikrein, and prevents the formation of cleaved high molecular weight kininogen (cHMWK) and bradykinin, thereby preventing HAE attacks. The clinical pharmacology of lanadelumab was characterized following subcutaneous administration in 257 subjects (24 healthy subjects and 233 patients with HAE). The pharmacokinetics of lanadelumab were described using a one-compartment model with first-order rate of absorption and linear clearance, showing slow absorption and a long half-life (14.8 days). A covariate analysis retained body weight and health status on apparent clearance (CL/F) and body weight on volume of distribution (V/F). Population estimates of CL/F and V/F were 0.0249 L/hour (0.586 L/day) and 12.8 L, respectively. An indirect-response Imax model showed 53.7% maximum suppression in cHMWK formation with a low potential for interactions with concomitant medications (analgesic, anti-inflammatory, and antirheumatic medications). A 300 mg dose administered Q2W was associated with a mean steady-state minimum concentration (Cmin,ss ; 25.4 µg/mL) that was ~ 4.5-fold higher than the half-maximal inhibitory concentration for cHMWK reduction (5.71 µg/mL). Exposure-response analyses suggest that 300 mg Q2W dosing was associated with a significantly reduced HAE attack rate, prolonged time to first attack after treatment initiation, and lower need for concomitant medications. The response was comparable across patient body weight groups. Findings from this analysis support the dosing rationale for lanadelumab to prevent attacks in patients with HAE.

Population Pharmacokinetic-Pharmacodynamic Model of Serum Transthyretin Following Patisiran Administration.

Hereditary transthyretin-mediated amyloidosis is an inherited, rapidly progressive, life-threatening disease caused by mutated transthyretin (TTR) protein. Patisiran is a small interfering RNA (siRNA) formulated in a lipid nanoparticle that inhibits hepatic TTR protein synthesis by RNA interference. We have developed an indirect-response pharmacokinetic-pharmacodynamic model relating plasma siRNA (ALN-18328) levels to serum TTR reduction across five clinical studies. A sigmoidal function described this relationship, with estimated Hill coefficient of 0.548, and half maximal inhibitory concentration (IC50), IC80, and IC90 values of 9.45, 118.5, and 520.5 ng/mL, respectively. Following patisiran 0.3 mg/kg every 3 weeks (q3w), steady-state plasma ALN-18328 exposures were between IC80 and IC90, yielding average serum TTR reductions of 80%-90% from baseline. Covariate analysis indicated similar TTR reduction across evaluated intrinsic and extrinsic factors, obviating the need for dose adjustment. Modeling results support the recommended patisiran dosing schedule of 0.3 mg/kg q3w, with a maximum dose of 30 mg for patients weighing ≥100 kg.

Population Pharmacokinetics and Pharmacodynamics of Ontamalimab (SHP647), a Fully Human Monoclonal Antibody Against Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), in Patients With Ulcerative Colitis or Crohn's Disease.

Ontamalimab (SHP647) is a fully human, immunoglobulin G2 , antihuman mucosal addressin cell adhesion molecule-1 (MAdCAM-1) monoclonal antibody being developed for the treatment of ulcerative colitis (UC) and Crohn's disease (CD). A population pharmacokinetic/pharmacodynamic (PK/PD) analysis was conducted using clinical phase 2 study data to evaluate the PK and PD of ontamalimab following subcutaneous administrations of 7.5, 22.5, 75, and 225 mg every 4 weeks in patients with moderate to severe UC or CD. A total of 440 patients with UC (n = 249; 56.6%) or CD (n = 191; 43.4%) were included in the analysis. A 2-compartment model with parallel linear and nonlinear elimination adequately characterized concentration-time profiles of ontamalimab. The apparent clearance and volume of distribution were 0.0127 L/h (0.305 L/day) and 6.53 L, respectively. Apparent clearance and volume of distribution were mainly dependent on baseline albumin and body weight, respectively. No differences in the PK properties of ontamalimab were observed between patients with UC or CD. The presence of antidrug antibodies did not impact the PK of ontamalimab. Nonlinear elimination occurred at very low concentrations and was unlikely to contribute to the elimination half-life under steady-state conditions. A linear PK/PD model described the relationship between ontamalimab and free MAdCAM-1. Minimum concentrations of ontamalimab at steady state following 75 mg every 4 weeks were associated with >95% suppression of circulating free MAdCAM-1. The PK/PD properties characterized support phase 3 testing in UC and CD.

Pharmacokinetic profile of defibrotide in patients with renal impairment.

Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is an unpredictable, potentially life-threatening complication of hematopoietic stem cell transplant conditioning. Severe VOD/SOS, generally associated with multiorgan dysfunction (pulmonary or renal dysfunction), may be associated with >80% mortality. Defibrotide, recently approved in the US, has demonstrated efficacy treating hepatic VOD/SOS with multiorgan dysfunction. Because renal impairment is prevalent in patients with VOD/SOS, this Phase I, open-label, two-part study in adults examined the effects of hemodialysis and severe or end-stage renal disease (ESRD) on defibrotide pharmacokinetics (PK). Part 1 compared defibrotide PK during single 6.25 mg/kg doses infused with and without dialysis. Part 2 assessed defibrotide plasma PK after multiple 6.25 mg/kg doses in nondialysis-dependent subjects with severe/ESRD versus healthy matching subjects. Among six subjects enrolled in Part 1, percent ratios of least-squares mean and 90% confidence intervals (CIs) on dialysis and nondialysis days were 109.71 (CI: 97.23, 123.78) for maximum observed plasma concentration (Cmax); 108.39 (CI: 97.85, 120.07) for area under the concentration-time curve to the time of the last quantifiable plasma concentration (AUC0-t); and 109.98 (CI: 99.39, 121.70) for AUC extrapolated to infinity (AUC0-∞). These ranges were within 80%-125%, indicating no significant effect of dialysis on defibrotide exposure/clearance. In Part 2, defibrotide exposure parameters in six subjects with severe/ESRD after multiple doses (AUC0-t, 113 µg·h/mL; AUC over dosing interval, 113 µg·h/mL; Cmax, 53.8 µg/mL) were within 5%-8% of parameters after the first dose (AUC0-t, 117 µg·h/mL; AUC0-∞, 118 µg·h/mL; Cmax, 54.9 µg/mL), indicating no accumulation. Defibrotide peak and extent of exposures in those with severe/ESRD were ~35%-37% and 50%-60% higher, respectively, versus controls, following single and multiple doses. One adverse event (vomiting, possibly drug-related) was reported. These findings support defibrotide prescribing guidance stating no dose adjustment is necessary for hemodialysis or severe/ESRD.

Population pharmacokinetic analysis of thrombomodulin alfa to support dosing rationale in patients with renal impairment.

Thrombomodulin alfa is a soluble recombinant human thrombomodulin that was reported to enhance the reversal of disseminated intravascular coagulation (DIC) in subjects with sepsis or hematologic malignancy and reduce mortality in subjects with sepsis and DIC. Population pharmacokinetic (PK) analysis of thrombomodulin alfa was performed based on rich samples collected in 24 healthy subjects (0.02 and 0.06 mg/kg) and sparse samples collected in 368 subjects with sepsis and DIC (0.06 mg/kg). Sources of variability (baseline characteristics, markers of renal/liver function, hematocrit, and disease severity) were explored using non-linear mixed effect modeling to support dosing rationale in patients with sepsis and DIC. Plasma concentrations of thrombomodulin alfa were best fitted with a one-compartment model. Body weight and creatinine clearance were important covariates describing the PK of thrombomodulin alfa. Typical CL values in patients with normal renal function, or mild, moderate and severe renal impairment were 0.158, 0.145, 0.128, and 0.105 L/h, respectively. Based on simulations, a 0.06 mg/kg dosing of thrombomodulin alfa is expected to result in drug exposure within the therapeutic range of the product (300-5,400 ng/mL), with minimum risks of bleeding in patient with normal and impaired renal functions.

Exposure-response analysis of pertuzumab in HER2-positive metastatic breast cancer: absence of effect on QTc prolongation and other ECG parameters.

PURPOSE: The phase III trial of pertuzumab plus trastuzumab plus docetaxel versus placebo plus trastuzumab plus docetaxel for first-line treatment of HER2-positive metastatic breast cancer included a substudy to determine whether pertuzumab affected the corrected QT (QTc) interval or other electrocardiogram parameters. METHODS: Triplicate 12-lead electrocardiogram measurements and serum samples were collected before (-30 and -15 min) and after (0-15 and 60-75 min) pertuzumab/placebo infusions (Cycles 1 and 3), and at 72 h post-infusion (Cycle 1). Fridericia's correction was applied to QT measurements (QTcF) and change from baseline (ΔQTcF) calculated. Statistical analyses were performed on baseline-adjusted, placebo-corrected QTcF values (ΔΔQTcF). Linear mixed-effects modeling evaluated potential exposure-response relationships between ΔQTcF and observed pertuzumab concentrations. RESULTS: Thirty-seven female patients participated in the substudy. QTcF values in both groups were within the normal range and below critical thresholds of clinical concern. No pertuzumab-treated patient showed abnormal electrocardiogram morphology. In Cycle 1, mean ΔΔQTcF (90 % CI) values at 0-15 min, 60-75 min, and 72 h post-infusion were -6.96 (-13.69, -0.23), -6.35 (-13.57, 0.88), and -4.08 (-12.64, 4.48), all of which were <5 ms, with upper CI limits <10 ms. One Cycle 3 post-infusion mean ΔΔQTcF value exceeded 5 ms. Other electrocardiogram parameters were within normal ranges. Concentration-QTc modeling showed no apparent relationship between ΔQTcF and pertuzumab concentrations. CONCLUSIONS: Cardiac monitoring and concentration-QTc modeling demonstrated that pertuzumab, combined with trastuzumab and docetaxel, had no clinically relevant effects on QTcF and other electrocardiogram parameters.

Absence of pharmacokinetic drug-drug interaction of pertuzumab with trastuzumab and docetaxel.

Pertuzumab is a novel antihuman epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody. Combined with trastuzumab plus docetaxel, pertuzumab improved progression-free and overall survival versus trastuzumab plus docetaxel in the phase III CLEOPATRA trial (NCT00567190) in first-line HER2-positive metastatic breast cancer. Thirty-seven patients participated in a pharmacokinetic (PK)/corrected QT interval substudy of CLEOPATRA, which evaluated potential PK drug-drug interaction (DDI). PK parameters were calculated using noncompartmental methods, and DDI analyses were carried out. In the presence of trastuzumab and docetaxel, the mean pertuzumab Cmin and Cmax in cycle 3 were 63.6 and 183 µg/ml, respectively. The pertuzumab concentrations observed were consistent with simulations from a validated population PK model, indicating that trastuzumab and docetaxel did not alter pertuzumab PK. Comparison of geometric least-squares mean PK parameters between arms showed no impact of pertuzumab on the PK of trastuzumab or docetaxel. In conclusion, no PK DDI was observed when pertuzumab, trastuzumab, and docetaxel were combined for the treatment of HER2-positive metastatic breast cancer.

Pharmacokinetics of SN2310, an injectable emulsion that incorporates a new derivative of SN-38 in patients with advanced solid tumors.

SN2310 is an injectable emulsion composed of vitamin E, a succinate derivative, as well as 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan. Single intravenous doses of 15, 20, 25, and 30 mg/m(2) of SN2310 emulsion were administered in a total of 26 patients with advanced solid malignancies. Serial blood samples were collected and concentrations of SN2310, SN-38, and SN-38 glucuronide were assayed. Mean systemic clearance of SN2310 ranged between 1.91 and 2.02 L/h/m(2) . Peak concentrations of SN-38 were observed at the end of infusion, suggesting a fast metabolic conversion of SN2310 to its active form, SN-38. Mean t1/2 values of SN-38 across the 20-30 mg/m(2) dose levels (131-199 h) were 33-55-fold longer than those observed for SN2310. The systemic exposure of SN-38 increased in a proportional manner over the dose range studied. SN2310 emulsion displayed an improved safety profile as compared with irinotecan. The most significant safety risk was neutropenia. Considering the rapid formation of SN-38, the proportional increase in exposure levels, and its longer elimination half-life, less frequent dosing of SN2310 emulsion may be considered for the treatment of patients with advanced solid malignancies.

Population pharmacokinetics of teduglutide following repeated subcutaneous administrations in healthy participants and in patients with short bowel syndrome and Crohn's disease.

Teduglutide is a GLP-2 analog currently evaluated for the treatment of short bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1-compartment model with a site-specific rate constant of absorption in the abdomen, arm, and thigh was used to assess the PK of teduglutide. Apparent clearance (CL/F) of teduglutide in male participants was approximately 18% higher than that observed in female participants (12.4 vs 10.5 L/h, respectively). Body weight was detected as a significant covariate explaining the volume of distribution of teduglutide. The elimination half-life (t((1/2))) of teduglutide was also influenced by the body weight of participants. For a male patient weighing 50 and 90 kg, t((1/2)) of teduglutide was 0.897 and 2.99 hours, respectively. Renal and hepatic function of patients did not affect the PK of teduglutide. As a result, no dose adjustment was deemed necessary in patients with altered renal or liver function. The population PK model will help to support adequate drug labeling following SC administrations in patients and determine whether an individualized dosage is required.

Pharmacokinetics, safety, and tolerability of teduglutide, a glucagon-like peptide-2 (GLP-2) analog, following multiple ascending subcutaneous administrations in healthy subjects.

Teduglutide, a glucagon-like peptide-2 (GLP-2) analog, is currently being evaluated for the treatment of short-bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The pharmacokinetics, safety, and tolerability of teduglutide in healthy subjects (N = 64) were assessed following daily subcutaneous administrations for 8 days in a double-blinded, randomized, placebo-controlled, ascending-dose study. Teduglutide treatments were administered as a 50-mg/mL (10, 15, 20, 25, 30, 50, and 80 mg) or 20-mg/mL (20 mg) formulation. Blood samples were collected on days 1 and 8, and plasma concentrations of teduglutide were measured using a liquid chromatography/tandem mass spectrometry method. Mean systemic exposures to teduglutide were very similar on days 1 and 8, suggesting minimal, if any, accumulation following once-daily repeated administrations. The apparent clearance of teduglutide following administration of the 50-mg/mL formulation was constant over the dose range, with mean values in male and female subjects of 0.155 and 0.159 L/h/kg, respectively. Peak plasma concentrations and total exposure of teduglutide after subcutaneous injection of a 20-mg/mL formulation (1.0 mL) were approximately 15% and 78% higher than those observed with the 50-mg/mL formulation (0.4 mL), respectively. Teduglutide treatments were safe and well tolerated. All but 1 adverse event was assessed as mild or moderate in severity. No relationship between teduglutide treatments and frequency of adverse events was observed, with the exception of injection site pain, which increased as a function of dose and injected volume. Results from the current study will assist in the dose selection in future efficacy studies.

Production of ex vivo lipopolysaccharide-induced tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 is suppressed by trans-resveratrol in a concentration-dependent manner.

Trans-resveratrol is a biologically active compound present in certain foods that has anti-inflammatory and anticancer properties. These beneficial effects are derived from both the immune system and cytokines. The purpose of this study was to determine the immunomodulatory effect of trans-resveratrol on the ex vivo production of inflammatory and anti-inflammatory cytokines stimulated by lipopolysaccharides (LPS). Trans-resveratrol (0, 0.01, 0.1, 1, and 10 microM) was added to blood samples from male Sprague-Dawley rats (n = 6) along with 100 U of LPS (Escherichia coli serotype, 055B5). The samples were then incubated for 4 h at 37 degrees C and centrifuged. Finally, concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 in the plasma were analyzed using an enzyme-linked immunosorbent assay (ELISA). The production of inflammatory (TNF-alpha and IL-1beta) and anti-inflammatory (IL-6) cytokines was suppressed by trans-resveratrol in a concentration-dependent manner. These results support the hypothesis that the immunomodulatory effect of trans-resveratrol plays an important role in disease conditions that involve an overproduction of inflammatory cytokines.

Pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin after intratracheal administration in rats with pulmonary Burkholderia cepacia infection.

The objective of the present study was to determine the pharmacokinetics and efficacies of liposomal and conventional formulations of tobramycin against Burkholderia cepacia in a model of chronic lung infection. Male Sprague-Dawley rats were inoculated intratracheally with 10(6) CFU of a very resistant strain of B. cepacia (strain BC 1368; MIC, 128 micro g/ml) to establish lung infection. A 1,200- micro g dose of tobramycin was administered intratracheally as a liposomal formulation and as a conventional formulation. Rats were anesthetized and exsanguinated by cardiac puncture at different times over 24 h to assess pulmonary tobramycin concentrations and the number of residual CFU. Pharmacokinetic parameters were calculated by using a two-compartment model with NONMEM. The mean half-life at the beta phase (t(1/2beta)) and the pulmonary exposure (the area under the concentration-time curve [AUC]) of liposomal tobramycin were 19.7 h (coefficient of variation [CV], 24.2%) and 6,811 micro g. h/lungs (CV, 19.7%), respectively. The pharmacokinetics of conventional tobramycin were statistically different, with a t(1/2beta) and AUC of 12.9 h (CV, 31.4%) and 821 micro g. h/lungs (CV, 15.0%), respectively. Pearson chi-square analyses were performed on residual CFU data distributed in the following categories: <10(3), 10(3) to 10(5), and >10(5). Differences in CFU data between formulations showed a statistical trend (P < 0.10) when data from all time points were used, and statistically significant differences were found after 12 h (P < 0.05), with greater eradication achieved with the liposomal formulation. In conclusion, intratracheal administration of tobramycin in liposomes was associated with marked changes in the pharmacokinetics of the drug in the lung and an apparent trend for a prolonged efficacy against B. cepacia. These results support the hypothesis that inhalation of liposomal tobramycin may improve the management of chronic pulmonary infections caused by resistant bacteria in patients with cystic fibrosis.

Metabolism and disposition of resveratrol in rats: extent of absorption, glucuronidation, and enterohepatic recirculation evidenced by a linked-rat model.

Pharmacokinetics of trans-resveratrol in its aglycone (RES(AGL)) and glucuronide (RES(GLU)) forms were studied following intravenous (15 mg/kg i.v.) and oral (50 mg/kg p.o.) administration of trans-resveratrol in a solution of beta-cyclodextrin to intact rats. In addition, the enterohepatic recirculation of RES(AGL) and RES(GLU) was assessed in a linked-rat model. Multiple plasma and urine samples were collected and concentrations of RES(AGL) and RES(GLU) were determined using an electrospray ionization-liquid chromatography/tandem mass spectrometry method. After i.v. administration, plasma concentrations of RES(AGL) declined with a rapid elimination half-life (T(1/2), 0.13 h), followed by sudden increases in plasma concentrations 4 to 8 h after drug administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of RES(AGL) (T(1/2TER), 1.31 h). RES(AGL) and RES(GLU) also displayed sudden increases in plasma concentrations 4 to 8 h after oral administration, with T(1/2TER) of 1.48 and 1.58 h, respectively. RES(AGL) bioavailability was 38% and its exposure was approximately 46-fold lower than that of RES(GLU) (AUC(inf), 7.1 versus 324.7 micromol.h/l). Enterohepatic recirculation was confirmed in the linked-rat model since significant plasma concentrations of RES(AGL) and RES(GLU) were observed in bile-recipient rats at 4 to 8 h. The percentages of the exposures of RES(AGL) and RES(GLU) that were due to enterohepatic recirculation were 24.7 and 24.0%, respectively. The fraction of drug excreted in the urine over a period of 12 h was negligible. These results confirm that RES(AGL) is bioavailable and undergoes extensive first-pass glucuronidation, and that enterohepatic recirculation contributes significantly to the exposure of RES(AGL) and RES(GLU) in rats.