Errors-in-variables in joint population pharmacokinetic/pharmacodynamic modeling

Pharmacokinetic (PK) models describe the relationship between the administered dose and the concentration of drug (and/or metabolite) in the blood as a function of time. Pharmacodynamic (PD) models describe the relationship between the concentration in the blood (or the dose) and the biologic response. Population PK/PD studies aim to determine the sources of variability in the observed concentrations/responses across groups of individuals. In this article, we consider the joint modeling of PK/PD data. The natural approach is to specify a joint model in which the concentration and response data are simultaneously modeled. Unfortunately, this approach may not be optimal if, due to sparsity of concentration data, an overly simple PK model is specified. As an alternative, we propose an errors-in-variables approach in which the observed-concentration data are assumed to be measured with error without reference to a specific PK model. We give an example of an analysis of PK/PD data obtained following administration of an anticoagulant drug. The study was originally carried out in order to make dosage recommendations. The prior for the distribution of the true concentrations, which may incorporate an individual's covariate information, is derived as a predictive distribution from an earlier study. The errors-in-variables approach is compared with the joint modeling approach and more naive methods in which the observed concentrations, or the separately modeled concentrations, are substituted into the response model. Throughout, a Bayesian approach is taken with implementation via Markov chain Monte Carlo methods.     

Biomeasures and mechanistic modeling highlight PK/PD risks for a monoclonal antibody targeting Fn14 in kidney disease

Discovery of the upregulation of fibroblast growth factor-inducible-14 (Fn14) receptor following tissue injury has prompted investigation into biotherapeutic targeting of the Fn14 receptor for the treatment of conditions such as chronic kidney diseases. In the development of monoclonal antibody (mAb) therapeutics, there is an increasing trend to use biomeasures combined with mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modeling to enable decision making in early discovery. With the aim of guiding preclinical efforts on designing an antibody with optimized properties, we developed a mechanistic site-of-action (SoA) PK/PD model for human application. This model incorporates experimental biomeasures, including concentration of soluble Fn14 (sFn14) in human plasma and membrane Fn14 (mFn14) in human kidney tissue, and turnover rate of human sFn14. Pulse-chase studies using stable isotope-labeled amino acids and mass spectrometry indicated the sFn14 half-life to be approximately 5 hours in healthy volunteers. The biomeasures (concentration, turnover) of sFn14 in plasma reveals a significant hurdle in designing an antibody against Fn14 with desired characteristics. The projected dose (>1 mg/kg/wk for 90% target coverage) derived from the human PK/PD model revealed potential high and frequent dosing requirements under certain conditions. The PK/PD model suggested a unique bell-shaped relationship between target coverage and antibody affinity for anti-Fn14 mAb, which could be applied to direct the antibody engineering towards an optimized affinity. This investigation highlighted potential applications, including assessment of PK/PD risks during early target validation, human dose prediction and drug candidate optimization.     

Animal models in the pharmacokinetic/pharmacodynamic evaluation of antimicrobial agents

Animal infection models in the pharmacokinetic/pharmacodynamic (PK/PD) evaluation of antimicrobial therapy serve an important role in preclinical assessments of new antibiotics, dosing optimization for those that are clinically approved, and setting or confirming susceptibility breakpoints. The goal of animal model studies is to mimic the infectious diseases seen in humans to allow for robust PK/PD studies to find the optimal drug exposures that lead to therapeutic success. The PK/PD index and target drug exposures obtained in validated animal infection models are critical components in optimizing dosing regimen design in order to maximize efficacy while minimize the cost and duration of clinical trials. This review outlines the key components in animal infection models which have been used extensively in antibiotic discovery and development including PK/PD analyses.     

Quantitative analysis of PD 0332991 in mouse plasma using automated micro-sample processing and microbore liquid chromatography coupled with tandem mass spectrometry

In the oncology therapeutic area, the mouse is the primary animal model used for efficacy studies. Often with mouse pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) studies, less than 20 μL of total plasma sample volume is available for bioanalysis due to the small size of the animal and the need to split samples for other measurements such as biomarker analyses. The need to conduct automated "small volume" sample processing for quantitative bioanalysis has therefore increased. An automated fit for purpose protein precipitation (PPT) method using a Hamilton MicroLab Star (Reno, NV, USA) to support mouse PK and PK/PD studies for an oncology drug candidate PD 0332991, (a specific inhibitor of cyclin-dependent kinase 4 (CDK-4) currently in development) for processing "small volumes" was developed. The automated PPT method was achieved by extracting and processing 10 μL out of a minimum sample volume of 15 μL plasma utilizing the Hamilton MicroLab Star. A 96-conical shallow well plate by Agilent Technologies, Inc (Wilmington, DE, USA) was the labware of choice used in the automated Hamilton "small volume" method platform. Analyses of a 10 μL plasma aliquot from 15 μL of plasma study samples were conducted by both automated and manual PPT method. All plasma samples were quantitated using a Sciex API 4000 triple quadrupole mass spectrometer coupled with an Eksigent Express HT Ultra HPLC system. The chromatography was achieved using an Agilent microbore C(18) Extend, 1.0 × 50 mm, 3.5 μm column at a flow rate of 0.150 mL/min with a total run time of 1.8 min. Accuracy and precision of standard and QC concentration levels were within 90-107% and <14%, respectively. Calibration curves were linear over the dynamic range of 1.0-1000 ng/mL. PK studies for PD 0332991 were conducted in female C3H mice following intravenous administration at 1mg/kg and oral administration at 2mg/kg. PK values such as area under curve (AUC), volume of distribution (Vd), clearance (Cl), half life (T(1/2)) and bioavailability (F%) demonstrated less than 11% difference between the automated Hamilton and manual PPT methods. The results demonstrate that the automated Hamilton PPT method can accurately and precisely aliquot 10 μL of plasma from 15 μL or larger volume plasma samples. The fit for purpose Hamilton PPT method is suitable for routine analyses of plasma samples from micro-sampling PK and PK/PD samples to support discovery studies.     

Combinations of anticancer drugs and immunotherapy

Immunotherapy (biological therapy) comprises such things as active specific immunotherapy ("cancer vaccines"), nonspecific immunostimulation with cytokines, and the inhibition of suppressor influences exerted or elicited by the tumor. Just as cancer chemotherapy began with the use of single agents and evolved into combination therapy, so immunotherapeutic agents have been combined with each other and with chemotherapy. The alkylating agent cyclophosphamide (Cytoxan; CYC) has been used for many years to inhibit tumor-derived suppressor influences in rodents, and has been exploited for the same use in humans. Combinations of CYC and cancer vaccines such as autologous tumor cells, Melacine, large multivalent immunogen (LMI), and Theratope have been tested with some success in humans for more than a decade. In this use, the CYC is a biological response modifier rather than an antitumor agent, intended to inhibit suppressor influences. CYC and low- to moderate-dose IL-2 has also been a useful regimen in treating human melanomas. IL-2 is itself a useful component of combination immunotherapy, such as with melanoma peptide vaccines, or with interferon -2b, (IFN-), as a dual combination or part of a biochemotherapy regimen. Several different combinations of drugs and biological agents have been used as biochemotherapy for melanoma, but although there are higher response (regression) rates the long-range survival benefits have been marginal, not justifying the severe toxicity. Combinations of 5-fluorouracil (5-FU) and IFN- or levamisole have had efficacy in colon and head and neck cancers, but here the biological agents have been biochemical modulators, not immunotherapy. Although experience with combinations of monoclonal antibodies and chemotherapy has been limited, it appears that trastuzumab (Herceptin) potentiates antitumor therapy in breast cancer but also increases the cardiotoxicity of those regimens.This article forms part of the Symposium in Writing on "Cellular immunity for cancer chemoimmunotherapy" in Volume 52 (2003)     

Antitumor effects of the combination immunotherapy with interleukin-12 and tumor necrosis factor α in mice

 There is strong evidence that antitumor activity of interleukin-12 (IL-12) in vivo is mediated, in part, through interferon (IFNγ) produced by IL-12-stimulated natural killer and T cells. Since IFNγ and tumor necrosis factor α (TNFα) have been reported to synergize in antitumor effects in a number of models, we decided to examine whether the combined treatment with recombinant mouse IL-12 and recombinant human TNFα would produce similar effects. The efficacy of the combined IL-12/TNFα immunotherapy was evaluated in three tumor models in mice: B16F10 melanoma, Lewis lung (LL/2) carcinoma and L1 sarcoma. Intratumoral daily injections of 1 μg IL-12 in combination with 5 μg TNFα into B16F10-melanoma-bearing mice resulted in a significant retardation of the tumor growth as compared with that in controls and in mice treated with either cytokine alone. Similar effects were obtained using 0.1 μg IL-12 and 5 μg TNFα in LL/2 carcinoma and L1 sarcoma models. Antitumor activity against L1 sarcoma was still preserved when TNFα at a low dose (1 μg) was combined with 0.1 μg IL-12 and applied for a prolonged time. Potentiation of antitumor effects, which was observed in IL-12/TNFα-based immunotherapy, could result from at least three different mechanisms, partly related to stimulation of IFNγ and TNFα production in treated mice: (a) direct cytostatic/cytotoxic effects on tumor cells, (b) induction of antitumor activity of macrophages, and (c) inhibition of blood vessel formation in the tumor. Our studies demonstrate that combination tumor immunotherapy with IL-12 and TNFα may be more effective than single-cytokine treatment, and suggest possible mechanisms by which IL-12 and TNFα may exert potentiated therapeutic effects against locally growing tumors. Received: 17 February 1997 / Accepted: 5 August 1997     

Comparison of three oral selenium compounds in cancer patients: Evaluation of differential pharmacodynamic effects in normal and malignant cells

BackgroundSelenium (Se) compounds have demonstrated therapeutic synergism in combination with anticancer treatments whilst reducing normal tissue toxicities in a range of experimental models. While reduction in some toxicities of chemotherapy and radiation has been confirmed in randomised clinical trials, they have not been powered to evaluate improved anticancer efficacy. A lack of data on the clinical potencies of the main nutritionally-relevant forms of Se and the relationship between their pharmacokinetic (PK) profiles and pharmacodynamic (PD) effects in cancer patients has hampered progress to date.The primary objective of this study was to determine the dose and form of Se that can be most safely and effectively used in clinical trials in combination with anti-cancer therapies.Study methodsIn a phase I randomised double-blinded study, the PD profile of sodium selenite (SS), Se-methylselenocysteine (MSC) and seleno-l-methionine (SLM) were compared in two cohorts of 12 patients, one cohort with chronic lymphocytic leukaemia (CLL) and the other with solid malignancies. All 24 patients were randomised to receive 400 μg of elemental Se as either SS, MSC or SLM, taken orally daily for 8 weeks. PD parameters were assessed before, during and 4 weeks after Se compound exposure in plasma and peripheral blood mononuclear cells (PBMCs).ResultsNo significant sustained changes were observed in plasma concentrations of vascular endothelial growth factor-α (VEGF-α), expression of proteins associated with endoplasmic reticulum stress (the unfolded protein response) or in intracellular total glutathione in PBMCs, in either disease cohort or when grouped by Se compound.ConclusionsAt the 400 μg dose level no substantial changes in PD parameters were noted. Extrapolating from pre-clinical data, the dose examined in this cohort was too low to achieve the Se plasma concentration (≥ 5 μM) expected to elicit significant PD effects. Recruitment of a subsequent cohort at higher doses to exceed this PK threshold is planned.     

Integrated pharmacokinetic,pharmacodynamic and immunogenicity profiling of an anti-CCL21 monoclonal antibody in cynomolgus monkeys

QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359. We have shown by means of PK/PD modeling that clearance of mAb-ligand complex is the most likely explanation for the rapid clearance of QBP359 in cynomolgus monkey. IHC and liquid chromatography mass spectrometry data suggested a high turnover and synthesis rate of CCL21 in tissues. Although lymphoid tissue was expected to accumulate drug due to the high levels of CCL21 present, bioavailability following subcutaneous administration in monkeys was 52%. In human disease states, where CCL21 expression is believed to be expressed at 10-fold higher concentrations compared with cynomolgus monkeys, the PK/PD model of QBP359 and its binding to CCL21 suggested that very large doses requiring frequent administration of mAb would be required to maintain suppression of CCL21 in the clinical setting. This highlights the difficulty in targeting soluble proteins with high synthesis rates.     

Oseltamivir Population Pharmacokinetics in the Ferret: Model Application for Pharmacokinetic/Pharmacodynamic Study Design

The ferret is a suitable small animal model for preclinical evaluation of efficacy of antiviral drugs against various influenza strains, including highly pathogenic H5N1 viruses. Rigorous pharmacokinetics/pharmacodynamics (PK/PD) assessment of ferret data has not been conducted, perhaps due to insufficient information on oseltamivir PK. Here, based on PK data from several studies on both uninfected and influenza-infected groups (i.e., with influenza A viruses of H5N1 and H3N2 subtypes and an influenza B virus) and several types of anesthesia we developed a population PK model for the active compound oseltamivir carboxylate (OC) in the ferret. The ferret OC population PK model incorporated delayed first-order input, two-compartment distribution, and first-order elimination to successfully describe OC PK. Influenza infection did not affect model parameters, but anesthesia did. The conclusion that OC PK was not influenced by influenza infection must be viewed with caution because the influenza infections in the studies included here resulted in mild clinical symptoms in terms of temperature, body weight, and activity scores. Monte Carlo simulations were used to determine that administration of a 5.08 mg/kg dose of oseltamivir phosphate to ferret every 12 h for 5 days results in the same median OC area under the plasma concentration-time curve 0–12 h (i.e., 3220 mg h/mL) as that observed in humans during steady state at the approved dose of 75 mg twice daily for 5 days. Modeling indicated that PK variability for OC in the ferret model is high, and can be affected by anesthesia. Therefore, for proper interpretation of PK/PD data, sparse PK sampling to allow the OC PK determination in individual animals is important. Another consideration in appropriate design of PK/PD studies is achieving an influenza infection with pronounced clinical symptoms and efficient virus replication, which will allow adequate evaluation of drug effects.     

Optimization of interleukin-21 immunotherapeutic strategies

The recently discovered interleukin-21 (IL-21) shows strong tumor attenuation in preclinical studies, and is considered a promising cancer immunotherapy agent. Yet, to exploit its potential, therapeutic strategies must be designed to achieve adequate balance between several conflicting aspects. A mathematical model describing the IL-21-antitumor effects provided the basis for application of the optimization methodology, aimed at finding improved immunotherapeutic regimens. Both dosages and inter-dosing intervals were optimized while considering maximal efficacy, determined by reduction of tumor burden, and minimal toxicity, estimated by cumulative IL-21 doses applied. Simulations allowed to compute the optimal regimen and explore its dependence on the weights of the target function. Optimized schedules lead to substantial cancer regression even with relatively low drug concentrations. Collectively, administration times shifted towards treatment onset, and IL-21 intensities sequentially decreased. Interestingly, there was a certain window in which deviations in the total IL-21 dosage administered largely influenced tumor elimination. The findings emphasize the importance of early tumor detection and the critical consequence of the inter-dosing interval on therapeutic efficacy, as supported by similar research involving chemotherapy. Our work provides initial basis for identifying clinically applicable IL-21 therapeutic strategies with improved efficacy/toxicity ratios.     

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m² daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.     

Augmentation of antitumor effect on syngeneic murine solid tumors by an interleukin 2 slow delivery system,the IL-2 mini-pellet

We evaluated the antitumor effect of an interleukin 2 (IL-2) slow delivery system, the IL-2 mini-pellet, in two murine solid tumor models, and also investigated the enhancement of its therapeutic effect by serial administration. The IL-2 mini-pellet contains 1 × 106 units of IL-2 and releases it slowlyin vivo. In our experiment, the IL-2 mini-pellet was administered subcutaneously near the tumor site in combination with the intravenous injection of lymphokine-activated killer (LAK) cells. When this regimen was given on days 8 and 11 after the subcutaneous inoculation of Meth A fibrosarcoma into BALB/c mice, tumor growth was significantly inhibited (p < 0.05) compared to tumor growth in untreated controls. Moreover, the IL-2 mini-pellet alone was also effective in inhibiting tumor growth. In another experiment, MH134 hepatoma was inoculated into C3H/He mice. Both administration of the IL-2 minipellet alone and in combination with LAK cells resulted in complete tumor regression in four of five mice. In a third experiment, serial administration of the IL-2 mini-pellet at 3- or 5-day intervals prolonged the suppression of Meth A fibrosarcoma growth in BALB/c mice. These results suggested that the IL-2 mini-pellet could be applied to cancer immunotherapy and that its antitumor effect could be prolonged by serial administration.     

Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma

Blocking autophagy with hydroxychloroquine (HCQ) augments cell death associated with alkylating chemotherapy in preclinical models. This phase I study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with dose-intense temozolomide (TMZ) in patients with advanced solid malignancies. Forty patients (73% metastatic melanoma) were treated with oral HCQ 200 to 1200 mg daily with dose-intense oral TMZ 150 mg/m² daily for 7/14 d. This combination was well tolerated with no recurrent dose-limiting toxicities observed. An MTD was not reached for HCQ and the recommended phase II dose was HCQ 600 mg twice daily combined with dose-intense TMZ. Common toxicities included grade 2 fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). Partial responses and stable disease were observed in 3/22 (14%) and 6/22 (27%) patients with metastatic melanoma. In the final dose cohort 2/6 patients with refractory BRAF wild-type melanoma had a near complete response, and prolonged stable disease, respectively. A significant accumulation in autophagic vacuoles (AV) in peripheral blood mononuclear cells was observed in response to combined therapy. Population pharmacokinetics (PK) modeling, individual PK simulations, and PK-pharmacodynamics (PD) analysis identified a threshold HCQ peak concentration that predicts therapy-associated AV accumulation. This study indicates that the combination of high-dose HCQ and dose-intense TMZ is safe and tolerable, and is associated with autophagy modulation in patients. Prolonged stable disease and responses suggest antitumor activity in melanoma patients, warranting further studies of this combination, or combinations of more potent autophagy inhibitors and chemotherapy in melanoma.     

A mechanistic PK/PD model for two anti-IL13 antibodies explains the difference in total IL-13 accumulation observed in clinical studies

IMA-638 and IMA-026 are humanized IgG1 monoclonal antibodies (mAbs) that target non-overlapping epitopes of IL-13. Separate first-in-human single ascending dose studies were conducted for each mAb. These studies had similar study designs, but mild to moderate asthmatics were recruited for the IMA-638 study and healthy subjects were recruited for the IMA-026 study. IMA-638 and IMA-026 showed similar pharmacokinetic (PK) profiles, but very different total IL-13 (free and drug bound IL-13) profiles; free IL13 was not measured. IMA-026 treatment induced a dose-dependent accumulation of total IL-13, while IMA-638 treatment led to a much smaller accumulation without any clear dose-response. To understand the differences between the two total IL-13 profiles and to predict the free IL-13 profiles for each mAb treatment, a mechanistic PK/pharmacodynamic model was developed. PK-related parameters were first fit to the mean PK profiles of each mAb separately; thereafter, the target-related parameters were fit to both total IL-13 profiles simultaneously. The IL-13 degradation rate was assumed to be the same for asthma patients and healthy subjects. The model suggests that an approximately 100× faster elimination of IL-13-IMA-638 complex than IL-13-IMA-026 complex could be responsible for the differences observed in total IL-13 profiles for the two mAbs. Furthermore, the model predicts that IMA-638 administration results in greater and more prolonged free IL-13 inhibition than equivalent dosing of IMA-026 despite similar binding K_D and PK profile. In conclusion, joint modeling of two similar molecules provided mechanistic insight that the elimination rate of mAb-target complex can regulate the degree of free target inhibition.     

Recombinant IL-21 and anti-CD4 antibodies cooperate in syngeneic neuroblastoma immunotherapy and mediate long-lasting immunity

IL-21 is an immune-enhancing cytokine, which showed promising results in cancer immunotherapy. We previously observed that the administration of anti-CD4 cell-depleting antibody strongly enhanced the anti-tumor effects of an IL-21-engineered neuroblastoma (NB) cell vaccine. Here, we studied the therapeutic effects of a combination of recombinant (r) IL-21 and anti-CD4 monoclonal antibodies (mAb) in a syngeneic model of disseminated NB. Subcutaneous rIL-21 therapy at 0.5 or 1 μg/dose (at days 2, 6, 9, 13 and 15 after NB induction) had a limited effect on NB development. However, coadministration of rIL-21 at the two dose levels and a cell-depleting anti-CD4 mAb cured 28 and 70 % of mice, respectively. Combined immunotherapy was also effective if started 7 days after NB implant, resulting in a 30 % cure rate. Anti-CD4 antibody treatment efficiently depleted CD4⁺ CD25^high Treg cells, but alone had limited impact on NB. Combination immunotherapy by anti-CD4 mAb and rIL-21 induced a CD8⁺ cytotoxic T lymphocyte response, which resulted in tumor eradication and long-lasting immunity. CD4⁺ T cells, which re-populated mice after combination immunotherapy, were required for immunity to NB antigens as indicated by CD4⁺ T cell depletion and re-challenge experiments. In conclusion, these data support a role for regulatory CD4⁺ T cells in a syngeneic NB model and suggest that rIL-21 combined with CD4⁺ T cell depletion reprograms CD4⁺ T cells from immune regulatory to anti-tumor functions. These observations open new perspectives for the use of IL-21-based immunotherapy in conjunction with transient CD4⁺ T cell depletion, in human metastatic NB.     

Simultaneous modeling of pharmacokinetics and pharmacodynamics: an improved algorithm

An algorithm and computer program is presented that fits a largelynon-parametric model to pharmacokinetic (PK) and pharmacodynamic(PD) data; it is an extension of a recently proposed approach.A PK model relates dose to plasma concentrations (Cp), a linkmodel relates plasma concentrations to the concentration inthe effect site (C_e), a PD model relates Ce to the effect. Boththe PK and the PD model are non-parametric, but the link modelis parametric. The extension presented here allows modelingof PK/PD data arising from non-steady-state experiments afterarbitrary dosage. In addition, several data sets from the sameindividual (or from different individuals) can now be analyzedsimultaneously, assuming the same link model for all, but allowingeither all the PD models to be the same, or all to be different. Received on March 15, 1987; accepted on July 27, 1987     

IFN-gamma mediates CD4+ T-cell loss and impairs secondary antitumor responses after successful initial immunotherapy

Protective cell-mediated immune responses in cancer are critically dependent on T-helper type 1 (T(H)1) cytokines such as interferon-gamma (IFN-gamma). We have previously shown that the combination of CD40 stimulation and interleukin-2 (IL-2) leads to synergistic antitumor responses in several models of advanced metastatic disease. We now report that after this treatment and other immunotherapy regimens, the CD4+ T-cell population, in contrast to CD8+ T cells, did not significantly increase but rather exhibited a substantial level of apoptosis that was dependent on IFN-gamma. Mice immunized with tumor cells and treated with an immunotherapy regimen that was initially protective were later unable to mount effective memory responses compared with immunized mice not receiving immunotherapy. Immunotherapy given to tumor-bearing Ifngr-/- mice resulted in restoration of secondary responses. Thus, although immunotherapeutic regimens inducing strong IFN-gamma responses can lead to successful early antitumor efficacy, they may also impair the development of durable antitumor responses.     

Comparative clinical pharmacokinetics of antibody-drug conjugates in first-in-human Phase 1 studies

Although there are currently more than 30 antibody-drug conjugates (ADC) in clinical development for the treatment of blood cancers and solid tumors, comparison of their clinical pharmacokinetics (PK) is challenging because of the large number of, and differences between, the targets, ADC constructs, dosing regimens, and patient populations. In this review, we standardized the evaluation, using non-compartmental PK data reported at Cycle 1, i.e., following the first drug administration of what is usually a repeated-dose treatment, in monotherapy. We report ADC clinical PK properties, dosing regimen, determination of doses ranges and associated maximum tolerated doses. We also evaluated the effect of structural characteristics and target types (hematological vs. solid tumors) on PK. In addition, we discuss how integration of PK/pharmacodynamics approaches on top of classical dose escalation in first-in-human studies may improve dosing regimen determination for subsequent phases of clinical development.     

Comparative clinical pharmacokinetics of antibody-drug conjugates in first-in-human Phase 1 studies

Although there are currently more than 30 antibody-drug conjugates (ADC) in clinical development for the treatment of blood cancers and solid tumors, comparison of their clinical pharmacokinetics (PK) is challenging because of the large number of, and differences between, the targets, ADC constructs, dosing regimens, and patient populations. In this review, we standardized the evaluation, using non-compartmental PK data reported at Cycle 1, i.e., following the first drug administration of what is usually a repeated-dose treatment, in monotherapy. We report ADC clinical PK properties, dosing regimen, determination of doses ranges and associated maximum tolerated doses. We also evaluated the effect of structural characteristics and target types (hematological vs. solid tumors) on PK. In addition, we discuss how integration of PK/pharmacodynamics approaches on top of classical dose escalation in first-in-human studies may improve dosing regimen determination for subsequent phases of clinical development.     

Some effects of medroxyprogesterone acetate on intermediary metabolism in rat liver.

This study examines the effects of MPA (medroxyprogesterone acetate) on some of the hepatic enzymes of carbohydrate and lipid metabolism in the rat, and compares these with the effects of cortisol and saline. Levels of reduced nicotinamide adenine dinucleotide phosphate (NADPH) were also measured. Intact mature female Wistar rats with average initial weight of 200 gms were injected with MPA (mO mg/kg IM) once a week for 4 weeks and were sacrificed 3 to 5 days after the last injection. Hydrocortisone (Solu-Cortef [R]) 40 mg/kg IM were given to cortisol-treated animals twice daily for 7 days. The animals were sacrificed 2-4 hours after the last dose was given. Normal saline (0.2 mg. IM) was injected in control animals twice a day. The method of Jellinek, Amako, and Willman was used to analyze NADPH. Liver samples were assayed for various enzymatic activities such as phophofructokinase (PFK); pyruvate kinase (PK), glycerol-3-phosphate dehydrogenase (G3PD), "malic" enzyme (ME), and glucose-6-phosphate dehydrogenase (G6PD). The methods of Colowick and Kaplan were used in enzymatic analyses. Lipogenic stimulation by MPA is indicated by increased levels of G3PD and ME, both of which are implicated in lipogenesis, as well as by NADPH. PFK, PK, and G6PD were all unaffected by the MPA regimen, suggesting that elevation of ME and NADPH activities may reflect increased amino acid conservation. The enzymatic pattern of MPA treatment shows lipogenesis and protein conservation, while that of cortisol regimen shows significantly lower levels of ME, G3PD, and PRK.