Developing a mechanistic translational PK/PD model for a trifunctional NK cell engager to predict the first-in-human dose for acute myeloid leukemia.

Natural killer cell engagers (NKCEs), a treatment that stimulates innate immunity, have lately gained attention owing to their favorable safety profile, and their efficacy. Natural killer (NK) cell activation is driven by immune synapse formation between drugs, NK cells, and tumor cells. However, no clear translational modeling approach has been reported for first-in-human (FIH) dose estimation of humanized NKCEs. We developed the first translational mechanistic synapse-driven pharmacokinetic/pharmacodynamic (PK/PD) model for a trifunctional NKp46/CD16a-CD123 (CD123-NKCE) by integrating (i) in vitro target cell cytotoxicity in MOLM-13 tumor cell lines at varying effector-to-tumor cell ratios and incubation intervals; (ii) nonhuman primate PK and profiles of CD123+ cells and NKP46+ NK cells; and (iii) healthy human or patients with acute myeloid leukemia system-specific parameters. To depict direct tumor cell killing by the innate immunity, no transit compartment was included in PK/PD model structures. Model predictions suggested an intrapatient dose escalation of 10/30/100 µg/kg twice weekly to be selected as the starting dose in the FIH trial. However, sensitivity analyses revealed that CD123+ cell growth rate constant and maximal tumor killing rate constant were the key uncertainties to the recommended active dose. This novel translational model structure can be used as the basis to predict clinical PK/PD data for CD123-NKCE, and the translational strategy may serve as a foundation for future advancements of NKCEs.

Population Pharmacokinetics of Tapentadol in Children from Birth to <18 Years Old.

OBJECTIVE: The main aim of this analysis was to characterize the pharmacokinetics (PK) of tapentadol in pediatric patients from birth to <18 years old who experience acute pain, requiring treatment with an opioid analgesic. PATIENTS AND METHODS: Data from four clinical trials and 148 pediatric patients who received a single dose of tapentadol oral or intravenous solution were included. Population PK analysis was performed to determine the contribution of size-related (bodyweight) and function-related (maturation) factors to the changes in oral bioavailability (F), volume of distribution (V), and clearance (CL) with age. Simulations were carried out to compare pediatric exposures to reference adult values. RESULTS: A one-compartment model with allometric scaling on disposition parameters (using theoretical or estimated exponents) and maturation functions on CL and F best described tapentadol PK. The estimated allometric exponents for CL (0.603) and V (0.820) differed slightly from the theoretical values of 0.75 for CL and 1 for V. A maximum in CL/F was observed at about 2-3 years when expressed on a bodyweight basis. Results for younger children as well as the F estimate were sensitive to the scaling approach, but CL/F and V/F as a function of age for the two scaling approaches led to similar curves within the bioequivalence range except below 5 weeks of age. Model-based simulations indicated that the doses used in the included clinical trials lead to exposures within the lower half of the targeted adult exposure. CONCLUSION: The development of tapentadol is one of the first examples following a systematic approach for analgesic drug development for children. Our analysis enabled a full characterization and robust understanding of tapentadol PK in children from birth to <18 years, including preterm infants, and showed the importance of evaluating the sensitivity of the inferences of the PK parameters to the selected scaling approach.

Pharmacokinetics of the Long-Acting Basal Insulin LY2605541 in Subjects With Varying Degrees of Renal Function.

The pharmacokinetics of LY2605541 (basal insulin peglispro), a novel long-acting basal insulin analogue, was evaluated in 5 groups of subjects with varying degrees of renal function based on creatinine clearance: normal renal function (>80 mL/min), mild renal impairment (51-80 mL/min), moderate renal impairment (30-50 mL/min), severe renal impairment (<30 mL/min), or end-stage renal disease (ESRD) requiring hemodialysis. Serial blood samples for pharmacokinetic analyses were collected up to 12 days following a single 0.33 U/kg subcutaneous dose of LY2605541. The apparent clearance (CL/F) and half-life across groups were not affected by renal function. Cmax values were lower in subjects with increasing severity of renal impairment; however, the small decrease in Cmax did not affect the overall exposure. Regression analysis showed that LY2605541 clearance is independent of renal function (slope = 0.000863; P = .885). The mean fraction of LY2605541 eliminated by a single hemodialysis session was 13% in subjects with ESRD. LY2605541 was generally well tolerated in healthy subjects and those with renal impairment following a single 0.33 U/kg subcutaneous dose. Given these data, no dose adjustment of LY2605541 based on pharmacokinetics is recommended in renal impairment or in patients undergoing hemodialysis.

Population exposure-response model to support dosing evaluation of ixekizumab in patients with chronic plaque psoriasis.

Ixekizumab (LY2439821), a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody that selectively binds and neutralizes interleukin (IL) 17A has demonstrated efficacy in the treatment of psoriasis. A population pharmacokinetics-pharmacodynamics model was developed using NONMEM 7.2 to describe the temporal relationship between ixekizumab concentrations and absolute Psoriasis Area and Severity Index (PASI) scores from a phase 2 dose-finding study in chronic plaque psoriasis. The objective was to inform dose-selection for further development. The primary endpoint, PASI 75 (75% or greater improvement from baseline PASI score) was then derived from each individual's absolute PASI score. The population pharmacokinetics of ixekizumab was characterized by a two-compartment model, while the exposure-response relationship was characterized using an indirect response model that described the pharmacological effects of ixekizumab and placebo in the form of inhibition of the formation of psoriatic skin lesions. PASI 75 responder status at the Week 12 primary endpoint was found to be a significant covariate on the concentration producing half maximal effect (EC50 ). While the results suggested patient may have different levels of sensitivity to ixekizumab, it is possible that nonresponder patients assigned to lower doses of ixekizumab may potentially become responders to ixekizumab if given doses that yield adequate exposures.

Single-dose pharmacokinetics and glucodynamics of the novel, long-acting basal insulin LY2605541 in healthy subjects.

LY2605541 is a novel basal insulin analog with a prolonged duration of action. Two Phase I studies assessed LY2605541 pharmacokinetics (PK), glucodynamics (GD), and tolerability in healthy subjects. In Study 1, 33 subjects received single subcutaneous (SC) doses of LY2605541 (0.01-2.22 U/kg) and insulin glargine (0.5-0.8 U/kg) followed by euglycemic clamp for up to 24-36 hours. In Study 2, absolute bioavailability of SC LY2605541 was assessed in 8 subjects by comparing dose normalized area under concentration versus time curve of SC against IV administration. Time-to-maximum plasma concentration (medians) and geometric means for half-life (t½ ) and apparent clearance, respectively, ranged from 18.0 to 42.0 hours, 24.4-45.5 hours, and 1.8-2.8 L/h for SC LY2605541, versus 10.0-12.0 hours, 12.2-14.9 hours, and 51.4-65.2 L/h for SC insulin glargine. LY2605541 glucose infusion rate (GIR) profiles were sustained for ≥36 hours versus glargine GIR profiles, which waned at 24 hours. After IV administration, LY2605541's geometric mean t½ was 2.3 hours. LY2605541 intra-subject variability (CV%) was <18% for PK and <32% for GD parameters. The most common adverse events were related to study procedures and were mild-moderate in severity. These results established a well-tolerated baseline dose for LY2605541 with a relatively flat PK profile and low intra-subject variability.

Basal insulin peglispro demonstrates preferential hepatic versus peripheral action relative to insulin glargine in healthy subjects.

OBJECTIVE: We evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects. RESEARCH DESIGN AND METHODS: This was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m(2)/min) in a fourth period, targeted to achieve 50-100% suppression of EGP. D-[3-(3)H] glucose was infused to assess rates of glucose appearance and disappearance. RESULTS: Mean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses. CONCLUSIONS: The novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects.