Studying navitoclax, a targeted anticancer drug, in healthy volunteers--ethical considerations and risk/benefit assessments and management.

BACKGROUND: Biopharmaceutical studies for anti-cancer drugs are typically conducted in cancer patients due to unacceptable toxicities to healthy volunteers. Navitoclax is a first-in-class, orally bioavailable, targeted Bcl-2 family protein inhibitor that has been studied in cancer patients. METHODS: A strategy that integrated the evaluation of non-clinical toxicology data and clinical data in cancer patients was employed to assess the feasibility, determine doses and establish risk management plans for studying navitoclax in healthy volunteers. Two relative bioavailability/food effect studies with either a 25 mg dose or 50 and 100 mg doses of navitoclax were conducted sequentially in healthy female volunteers of non-childbearing potential. RESULTS/CONCLUSION: Navitoclax was well-tolerated in both studies in healthy volunteers, and did not impose risks beyond the minimal levels expected in healthy volunteer studies. Compared to a similar study in cancer patients, the studies in healthy volunteers generated higher quality data in a short period of time to support formulation selection.

Pharmacokinetic and exposure-response analyses of leuprolide following administration of leuprolide acetate 3-month depot formulations to children with central precocious puberty.

BACKGROUND AND OBJECTIVE: A pharmacokinetic substudy was conducted within a phase 3 clinical trial that evaluated the efficacy and safety of two leuprolide acetate 3-month depot formulations in children with central precocious puberty (CPP), where the pharmacokinetics of leuprolide and the exposure-response relationship between leuprolide concentration and the probability of luteinizing hormone (LH) suppression were assessed. METHODS: Children diagnosed with CPP (N = 42 in each dosing cohort), who were treatment naïve or previously treated, received a total of two intramuscular injections of either leuprolide acetate depot 11.25 or 30 mg formulations administered 3 months apart. Serial blood samples were collected for leuprolide concentration determination in a subset of subjects (N = 24 in each cohort). One-way analysis of covariance was used to assess dose proportionality. The probability of LH suppression (peak-stimulated LH concentrations <4 mIU/mL) exposure-response relationship was modelled using repeated measures logistic regression. The predicted probability of LH suppression and the corresponding 95 % confidence interval at the mean leuprolide concentration of each dose group and at each time of measurement were computed. RESULTS: Mean leuprolide concentrations between weeks 4 and 12 for 11.25 and 30 mg doses were relatively constant and dose proportional, with no accumulation of leuprolide upon repeated administration. Body weight and age were not found to be significant covariates on leuprolide pharmacokinetics. Higher leuprolide concentrations were associated with higher probability of LH suppression and both doses provided LH suppression levels <4 mIU/mL. CONCLUSION: Leuprolide pharmacokinetics were characterized for 11.25 and 30 mg 3-month depot injections. An exposure-response model was developed to link leuprolide concentrations and probability of peak-stimulated LH suppression.

Evaluation of the pharmacokinetics and pharmacodynamics of two leuprolide acetate 45 mg 6-month depot formulations in patients with prostate cancer.

The pharmacokinetics (PK) and pharmacodynamics of two leuprolide acetate (LA) 45 mg 6-month depot formulations were characterized in prostate cancer patients. Subjects (planned N = 150 in each cohort) received two intramuscular injections of LA Formulation-A or Formulation-B administered 24 weeks apart. Samples were collected for the measurement of testosterone, LH (all subjects) and leuprolide (in a subset of subjects approximately N = 24 in each cohort) at the same time points. Leuprolide PK profile showed an initial peak followed by a rapid decline over the first week post-dose, with mean leuprolide concentrations staying relatively constant through the end of 24-week period. Mean testosterone and LH serum concentrations showed initial increases above baseline values after the first dose and then decreased to 16.0 ng/dL and 0.6 mIU/mL by Week 4 for Formulation-A and were maintained at ≤14.3 ng/dL and 0.4 mIU/mL, thereafter, with negligible mean increases after the second dose. Formulation-A showed a lower initial peak and higher leuprolide concentration during the sustained release phase which may explain higher testosterone suppression rates for Formulation-A compared to Formulation-B. Differences in PK between LA depot formulations were reflected in pharmacodynamic responses, with a higher rate of testosterone suppression and less escapes and acute-on-chronic responses for Formulation-A.

Exposure-response (safety) analysis to identify linifanib dose for a Phase III study in patients with hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths and the fifth most common cancer globally. Hepatocellular carcinoma produces highly vascular tumors that overexpress vascular endothelial growth factor (VEGF), thus making VEGF a promising therapeutic target. The competitive inhibitor linifanib (ABT-869) has selectivity for VEGF and platelet-derived growth factor (PDGF) receptors and minimal activity against unrelated tyrosine and serine and threonine kinases. However, the optimal dosing regimen for linifanib in HCC patients is not yet known. OBJECTIVE: This study attempts to identify a linifanib dose or dosing regimen with an acceptable safety profile for a Phase III study in HCC patients. METHODS: The pharmacokinetic (PK) properties of linifanib were characterized from 2 Phase I and 3 Phase II clinical trials. Of the 266 patients evaluated, the median weight was 68 kg (range, 35-177 kg), 64% were male, and 87.6% of patients received an oral solution of linifanib, whereas 12.4% received a tablet formulation. Approximately 95% of patients received drug based on weight, with the remaining on a fixed-dosing regimen. A population PK analysis was conducted to characterize the linifanib exposure for each patient. Linifanib Cmax and AUC derived from the population PK properties were correlated with the rates of adverse events (AEs). RESULTS: Linifanib PK properties are dose proportional for the 0.10-mg/kg to 0.25-mg/kg once daily dose range and are time independent after repeated oral dosing. The Tmax of linifanib is approximately 3 hours, and the t½ is approximately 1 day. The most common AEs related to linifanib PK were hypertension (P = 0.02 for Cmax and P = 0.01 for AUC), diarrhea (P = 0.001 for Cmax and P = 0.0012 for AUC), proteinuria (P = 0.001 for Cmax and P = 0.002 for AUC), and asthenia (P = 0.03 for AUC). Weight and sex were identified as covariates for Cmax, and sex was identified as a covariate for AUC. The predicted AE range for females was slightly higher compared with males; however, the AE range is tighter for the weight range for fixed dosing compared with weight-based dosing, regardless of sex. CONCLUSIONS: The PK properties of linifanib support a one-compartment model with first-order absorption and elimination. Comparison of weight-based and fixed dosing revealed predicted AE rates to be similar, with a tighter AE range for fixed dosing. The safety profile of linifanib, therefore, supports a 17.5 mg fixed starting dose for Phase III clinical studies.

Exposure-clinical response analysis of paricalcitol in patients with chronic kidney disease (stage 5) on hemodialysis or peritoneal dialysis.

Paricalcitol injection and capsules are approved for the prevention and treatment of secondary hyperparathyroidism. Exposure-response analyses were performed to describe paricalcitol pharmacokinetics and the relationship to clinical responses (intact parathyroid hormone [iPTH], serum calcium, and phosphorus) following administration of paricalcitol capsules or injection to patients with chronic kidney disease (stage 5). Paricalcitol pharmacokinetics were similar following intravenous and oral administration with mean oral clearance of 1.75 L/h and bioavailability of 75.1%. Exposure-clinical response was best described by an indirect effects model where serum iPTH, calcium, and phosphorus production rates were directly affected by paricalcitol. Significant covariates in the response model included screening iPTH, calcium, and phosphorus on their corresponding synthesis rates; age on iPTH EC(50); and bone-specific alkaline phosphatase on calcium EC(50) (CRIT). This exposure-response model was used in extensive clinical trial simulations to assess alternative dose regimens for CKD stage 5 patients.

Comparison of the gastrointestinal absorption and bioavailability of fenofibrate and fenofibric acid in humans.

This study compared the gastrointestinal (GI) absorption characteristics and absolute bioavailability of fenofibric acid and fenofibrate (which is converted to fenofibric acid in vivo) in healthy volunteers. Treatments were delivered to the proximal small bowel, distal small bowel, and colon using a site-specific delivery system (Enterion capsule) and to the stomach by oral administration of equimolar doses. Serial blood samples were collected for 120 hours postdose and assayed for plasma fenofibric acid concentrations. The absolute bioavailability of each treatment was determined relative to 50 mg of fenofibric acid administered intravenously. Plasma exposure to fenofibric acid following fenofibric acid administration was approximately 1.5 times higher than that following fenofibrate administration for delivery to the proximal and distal small bowel and following oral administration, and it was approximately 5 times higher following colon delivery. The absolute bioavailability in the stomach, proximal small bowel, distal small bowel, and colon was approximately 81%, 88%, 84%, and 78%, respectively, for fenofibric acid and 69%, 73%, 66%, and 22%, respectively, for fenofibrate (P < .0001 and P = .033 for fenofibric acid vs fenofibrate in the colon and distal small bowel, respectively). In conclusion, fenofibric acid is well absorbed throughout the GI tract and has greater bioavailability than fenofibrate in all GI regions.

ABT-335, the choline salt of fenofibric acid, does not have a clinically significant pharmacokinetic interaction with rosuvastatin in humans.

ABT-335 is the choline salt of fenofibric acid under clinical development as a combination therapy with rosuvastatin for the management of dyslipidemia. ABT-335 and rosuvastatin have different mechanisms of actions and exert complementary pharmacodynamic effects on lipids. The current study assessed the pharmacokinetic interaction between the 2 drugs following a multiple-dose, open-label, 3-period, randomized, crossover design. Eighteen healthy men and women received 40 mg rosuvastatin alone, 135 mg ABT-335 alone, and the 2 drugs in combination once daily for 10 days. Blood samples were collected prior to dosing on multiple days and up to 120 hours after day 10 dosing for the measurements of fenofibric acid and rosuvastatin plasma concentrations. Coadministering 40 mg rosuvastatin had no significant effect on the steady-state Cmax, Cmin, or AUC24 of fenofibric acid (P > .05). Coadministering ABT-335 had no significant effect on the steady-state Cmin or AUC24 of rosuvastatin (P > .05) but increased Cmax by 20% (90% confidence interval: 12%-28%). All 3 regimens were generally well tolerated with no clinically significant changes in clinical laboratory values, vital signs, or electrocardiograms during the study. Results from this study demonstrate no clinically significant pharmacokinetic interaction between ABT-335 at the full clinical dose and rosuvastatin at the highest approved dose.

Oral paricalcitol for the treatment of secondary hyperparathyroidism in patients on hemodialysis or peritoneal dialysis.

BACKGROUND/AIMS: Secondary hyperparathyroidism is a common complication of chronic kidney disease, resulting from inactivation of vitamin D receptor signaling and phosphate retention. Selective activation of vitamin D receptors with intravenous paricalcitol significantly reduced parathyroid hormone (PTH) levels with no significant hypercalcemia or hyperphosphatemia in predialysis and hemodialysis (HD) patients. This study investigates the effects of oral paricalcitol to reduce PTH in patients receiving chronic HD and peritoneal dialysis (PD). METHODS: Eighty-eight patients were randomized in double-blind fashion to receive paricalcitol or placebo for 12 weeks. The dose of the study drug was adjusted weekly using the previous week's intact PTH (iPTH) level as well as calcium and Ca x P product levels. The primary end points were efficacy (two consecutive iPTH decreases of >or=30%) and safety (two consecutive calcium measurements >11.0 mg/dl). Markers of biochemical bone activity were followed. RESULTS: Demographic characteristics were similar between treatment groups. The mean paricalcitol doses (three times a week) over the entire treatment period for subjects with baseline iPTH 500 pg/ml were 3.9 and 7.6 microg, respectively. A statistically significant decrease in iPTH was seen after week 1, with a mean 30% reduction occurring by week 3. A significantly greater proportion of both HD and PD paricalcitol subjects [83% (33/40) and 100% (18/18), respectively] achieved two consecutive >or=30% decreases in iPTH. The treatment groups were not statistically different in regard to the hypercalcemia safety end point. Phosphate binder use and mean serum phosphorus levels were not different between the treatment groups. The markers of bone activity improved in the treated subjects and worsened in those on placebo. CONCLUSION: Paricalcitol provides a rapid and sustained reduction of PTH in both HD and PD patients with minimal effect on serum calcium and phosphorus and no significant difference in adverse events as compared with placebo.

Effect of omeprazole on the pharmacokinetics of paricalcitol in healthy subjects.

Paricalcitol capsules are indicated for the prevention and treatment of secondary hyperparathyroidism in chronic kidney disease (CKD). Proton pump inhibitors are prescribed to CKD patients to treat gastroesophageal reflux. This was a single dose, crossover study evaluating the effect of omeprazole, change in gastric pH as a result thereof, on the pharmacokinetics (PK) of paricalcitol. Twenty-six healthy subjects were administered paricalcitol capsules (16 microg) alone (regimen A), and following a single dose of OMP (40 mg) (regimen B), with a washout of at least 7 days. Plasma samples for paricalcitol concentrations were collected for 48 h post-paricalcitol dose. The plasma paricalcitol concentrations were measured using an LC-MS/MS assay (LOQ=0.02 ng/ml) and paricalcitol pharmacokinetic parameters were estimated using non-compartmental methods. The point estimates and the corresponding 90% confidence intervals for Cmax and AUC0-infinity to evaluate paricalcitol-omeprazole interaction were 1.032 [0.920-1.158] and 1.041 [0.951-1.139], respectively. No significant differences in Tmax (regimen A: 2.9 h vs regimen B: 2.6 h) or t1/2 (6.83 h vs 6.6 h) between the regimens were observed. Hence, the co-administration of omeprazole does not affect the PK of paricalcitol. Both regimens were well tolerated and no apparent differences among the regimens with respect to safety were observed.

A comparison of dosing regimens of paricalcitol capsule for the treatment of secondary hyperparathyroidism in CKD stages 3 and 4.

BACKGROUND: Intermittent dosing of calcitriol for secondary hyperparathyroidism (SHPT) has been associated with greater parathyroid hormone (PTH) reduction with fewer calcemic and phosphatemic effects than daily (QD) dosing. METHODS: Secondary analyses of three randomized, double-blind, placebo-controlled multicenter studies in stage 3 and 4 chronic kidney disease (CKD) patients with SHPT were performed to compare three times per week (TIW) with QD dosing of paricalcitol. The pharmacokinetics of TIW and QD dosing of paricalcitol capsules were assessed in a separate group of healthy subjects. RESULTS: Pharmacokinetics revealed similar steady state paricalcitol exposure between dosing regimens. In CKD patients, baseline data were similar between the TIW studies (n = 72, paricalcitol; n = 73, placebo) and QD studies (n = 35, paricalcitol; n = 40, placebo). Both dosing regimens resulted in similar efficacy (91%) for the primary end point of two consecutive > or = 30% decreases in intact PTH from baseline, but the QD regimen resulted in a greater percent reduction in intact PTH from baseline. The chances for developing increased serum calcium and phosphorus levels or Ca x P product were similar between paricalcitol and placebo groups for both treatment regimens. Furthermore, no difference in the risk for these elevations was detected between the TIW and QD regimens. CONCLUSIONS: QD dosing of paricalcitol capsules is as efficacious as TIW dosing in achieving the primary end point (2 consecutive > or = 30% reductions in PTH) in stage 3 and 4 CKD patients with SHPT. Moreover, the QD regimen had no significant effect on hypercalcemia, hyperphosphatemia or Ca x P product as compared with placebo or intermittent dosing.

A phase I multiple-dose escalation study characterizing pharmacokinetics and safety of ABT-578 in healthy subjects.

ABT-578, a sirolimus analog, is being developed for administration from drug-eluting stents to prevent postimplantation neointimal hyperplasia. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of multiple doses of ABT-578. Healthy subjects randomly received placebo or ABT-578 (200, 400, or 800 microg) as daily intravenous infusions for 14 days. ABT-578 blood pharmacokinetics and urine excretion on days 1 and 14 were determined. The effect of ABT-578 on mitogen-stimulated lymphocyte proliferation was assessed. ABT-578 pharmacokinetics was described by a 3-compartment open model. The mean CL, V(ss), and t(1/2) ranges were 4.0 to 4.6 L/h, 92.5 to 118.0 L, and 24.7 to 31.0 hours, respectively. ABT-578 pharmacokinetics was dose and time invariant. Approximately 0.1% of ABT-578 was excreted in the urine. ABT-578 was well tolerated, and no systemic changes were observed in the mitogen-stimulated lymphocyte proliferation. ABT-578 was shown to be safe over a wide range of systemic exposures.