Pharmacometric Analysis of the Relationship Between Absolute Lymphocyte Count and Expanded Disability Status Scale and Relapse Rate, Efficacy End Points, in Multiple Sclerosis Trials.

The aim of this work was to assess the relationship between the absolute lymphocyte count (ALC), and disability (as measured by the Expanded Disability Status Scale [EDSS]) and occurrence of relapses, 2 efficacy endpoints, respectively, in patients with remitting-relasping multiple sclerosis. Data for ALC, EDSS, and relapse rate were available from 1319 patients receiving placebo and/or cladribine tablets. Pharmacodynamic models were developed to characterize the time course of the endpoints. ALC-related measures were then evaluated as predictors of the efficacy endpoints. EDSS data were best fitted by a model where the logit-linear disease progression is affected by the dynamics of ALC change from baseline. Relapse rate data were best described by the Weibull hazard function, and the ALC change from baseline was also found to be a significant predictor of time to relapse. Presented models have shown that once cladribine exposure driven ALC-derived measures are included in the model, the need for drug effect components is of less importance (EDSS) or disappears (relapse rate). This simplifies the models and theoretically makes them mechanism specific rather than drug specific. Having a reliable mechanism-specific model would allow leveraging historical data across compounds, to support decision making in drug development and possibly shorten the time to market.

Application of Item Response Theory to Modeling of Expanded Disability Status Scale in Multiple Sclerosis.

In this study, we report the development of the first item response theory (IRT) model within a pharmacometrics framework to characterize the disease progression in multiple sclerosis (MS), as measured by Expanded Disability Status Score (EDSS). Data were collected quarterly from a 96-week phase III clinical study by a blinder rater, involving 104,206 item-level observations from 1319 patients with relapsing-remitting MS (RRMS), treated with placebo or cladribine. Observed scores for each EDSS item were modeled describing the probability of a given score as a function of patients' (unobserved) disability using a logistic model. Longitudinal data from placebo arms were used to describe the disease progression over time, and the model was then extended to cladribine arms to characterize the drug effect. Sensitivity with respect to patient disability was calculated as Fisher information for each EDSS item, which were ranked according to the amount of information they contained. The IRT model was able to describe baseline and longitudinal EDSS data on item and total level. The final model suggested that cladribine treatment significantly slows disease-progression rate, with a 20% decrease in disease-progression rate compared to placebo, irrespective of exposure, and effects an additional exposure-dependent reduction in disability progression. Four out of eight items contained 80% of information for the given range of disabilities. This study has illustrated that IRT modeling is specifically suitable for accurate quantification of disease status and description and prediction of disease progression in phase 3 studies on RRMS, by integrating EDSS item-level data in a meaningful manner.

Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development.

The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.

Resistance Development: A Major Piece in the Jigsaw Puzzle of Tumor Size Modeling.

Mathematical models of tumor size (TS) dynamics and tumor growth inhibition (TGI) need to place more emphasis on resistance development, given its relevant implications for clinical outcomes. A deeper understanding of the underlying processes, and effective data integration at different complexity levels, can foster the incorporation of new mechanistic aspects into modeling approaches, improving anticancer drug effect prediction. As such, we propose a general framework for developing future semi-mechanistic TS/TGI models of drug resistance.

Boltzmann rovibrational collisional coarse-grained model for internal energy excitation and dissociation in hypersonic flows.

A Boltzmann rovibrational collisional coarse-grained model is proposed to reduce a detailed kinetic mechanism database developed at NASA Ames Research Center for internal energy transfer and dissociation in N(2)-N interactions. The coarse-grained model is constructed by lumping the rovibrational energy levels of the N(2) molecule into energy bins. The population of the levels within each bin is assumed to follow a Boltzmann distribution at the local translational temperature. Excitation and dissociation rate coefficients for the energy bins are obtained by averaging the elementary rate coefficients. The energy bins are treated as separate species, thus allowing for non-Boltzmann distributions of their populations. The proposed coarse-grained model is applied to the study of nonequilibrium flows behind normal shock waves and within converging-diverging nozzles. In both cases, the flow is assumed inviscid and steady. Computational results are compared with those obtained by direct solution of the master equation for the rovibrational collisional model and a more conventional multitemperature model. It is found that the proposed coarse-grained model is able to accurately resolve the nonequilibrium dynamics of internal energy excitation and dissociation-recombination processes with only 20 energy bins. Furthermore, the proposed coarse-grained model provides a superior description of the nonequilibrium phenomena occurring in shock heated and nozzle flows when compared with the conventional multitemperature models.

Nonequilibrium shock-heated nitrogen flows using a rovibrational state-to-state method.

A rovibrational collisional model is developed to study the internal energy excitation and dissociation processes behind a strong shock wave in a nitrogen flow. The reaction rate coefficients are obtained from the ab initio database of the NASA Ames Research Center. The master equation is coupled with a one-dimensional flow solver to study the nonequilibrium phenomena encountered in the gas during a hyperbolic reentry into Earth's atmosphere. The analysis of the populations of the rovibrational levels demonstrates how rotational and vibrational relaxation proceed at the same rate. This contrasts with the common misconception that translational and rotational relaxation occur concurrently. A significant part of the relaxation process occurs in non-quasi-steady-state conditions. Exchange processes are found to have a significant impact on the relaxation of the gas, while predissociation has a negligible effect. The results obtained by means of the full rovibrational collisional model are used to assess the validity of reduced order models (vibrational collisional and multitemperature) which are based on the same kinetic database. It is found that thermalization and dissociation are drastically overestimated by the reduced order models. The reasons of the failure differ in the two cases. In the vibrational collisional model the overestimation of the dissociation is a consequence of the assumption of equilibrium between the rotational energy and the translational energy. The multitemperature model fails to predict the correct thermochemical relaxation due to the failure of the quasi-steady-state assumption, used to derive the phenomenological rate coefficient for dissociation.

Pharmacokinetics and immunoglobulin response of subcutaneous and intravenous atacicept in patients with systemic lupus erythematosus.

Atacicept, a recombinant fusion protein of the TACI receptor and human IgG, is an inhibitor of B-Lymphocyte Stimulator (BLyS) and APRIL, potent stimulators of B cell maturation, proliferation, and survival. Pharmacokinetics (PKs) and biological activity of intravenous (iv) and subcutaneous (sc) atacicept are described here for patients with systemic lupus erythematosus in two randomized, double-blind, placebo-controlled, Phase Ib studies. Study 1: Six cohorts of eight patients received sc atacicept (single dose: 0.3, 1, 3, or 9 mg/kg; four weekly doses: 1 or 3 mg/kg), or placebo (3:1 ratio). Study 2: Four cohorts of six patients received iv atacicept (single dose: 3, 9, or 18 mg/kg; multiple dose: 2 x 9 mg/kg), or matching placebo (5:1 ratio). PK profiles were determined through serum atacicept and atacicept-BLyS complex, and biological activity through IgA, IgG, and IgM levels. PK profiles of atacicept were influenced by saturable binding between atacicept and its ligands, and were consistent and predictable across doses and regimens. Atacicept's biological activity was compatible with its presumed mechanism of action. Bioavailability was approximately 30-40% following sc or iv administration and similar doses yielded similar biological activity irrespective of administration route. This observation may have a mechanistic foundation and may inform dosing regimen design for future studies.

Atacicept in patients with rheumatoid arthritis: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating, single- and repeated-dose study.

OBJECTIVE: Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation-inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes. METHODS: In this multicenter, phase Ib, randomized, placebo-controlled, dose-escalating trial, 73 patients were enrolled into 6 escalating-dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2-week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose. RESULTS: Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment-related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti-citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose-related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3-month treatment. Little effect on the erythrocyte sedimentation rate or C-reactive protein levels was seen. CONCLUSION: Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.

Polyethylene glycol-conjugated growth hormone-releasing hormone is long acting and stimulates GH in healthy young and elderly subjects.

OBJECTIVE: The clinical use of growth hormone-releasing hormone (GHRH) is limited by its short half-life. Polyethylene glycol-conjugated GHRH (PEG-GHRH) was developed to provide increased stability compared with the currently available GHRH(1-29). This study aimed to evaluate the safety, tolerability and pharmacodynamics of PEG-GHRH. DESIGN: PEG-GHRH was administered by subcutaneous injection to young healthy men (n = 12) and elderly men and women (aged > 60 years; n = 20). RESULTS: In both groups, administration of PEG-GHRH generated a clear increase in circulating GH compared with placebo. Following single-dose (0.25, 0.5, 2 or 4 mg) administration to young subjects, the effect persisted for 12 h, but a sustained increase was observed on repeated administration to the elderly. Serum insulin-like growth factor-I also increased in response to PEG-GHRH treatment. Injection-site reactions were more frequent with PEG-GHRH compared with placebo, but these were mild and transient; other adverse events were similar to those observed after placebo. Some impairment of glucose tolerance was observed in the elderly following repeated administration of PEG-GHRH. Antibodies to GHRH were not observed. CONCLUSIONS: PEG-GHRH offers the possibility of less frequent dosing compared with GHRH. This possibility deserves further clinical testing.

Pharmacokinetics and pharmacodynamics of recombinant human chorionic gonadotrophin in healthy male and female volunteers.

The pharmacokinetics and pharmacodynamics of recombinant human chorionic gonadotrophin (rHCG) were investigated in three studies of healthy volunteers. After single intravenous doses of 25, 250 and 1000 microg, rHCG and urinary HCG (uHCG) showed linear pharmacokinetics described by a bi-exponential model, although the area under the curve (AUC) for uHCG was ~29% lower than for rHCG. After intramuscular or subcutaneous administration (absolute bioavailability, 40-50% for both), rHCG pharmacokinetics could be described by a first-order absorption, one-compartment model. During multiple subcutaneous dosing, the amount of HCG increased by approximately1.7-fold. A comparison of liquid and freeze-dried rHCG and freeze-dried uHCG showed pharmacokinetic bioequivalence. In down-regulated male subjects, single doses of 125 microg rHCG, given intravenously, intramuscularly or subcutaneously, produced comparable increases in serum testosterone, inhibin and 17beta-oestradiol, with little further increase during repeated subcutaneous administration (in female subjects, this produced a sustained comparable increase in serum androstenedione and testosterone concentrations). In conclusion, the pharmacokinetics and pharmacodynamics of rHCG are similar to those of uHCG and are not affected by the use of different formulations. In healthy subjects, rHCG produces pharmacodynamic responses consistent with HCG physiology and is suitable for use in the same clinical indications as uHCG. The secured source and high purity of rHCG may offer important advantages.

Leukemia inhibitory factor in human reproduction.

OBJECTIVE: To describe the clinical findings, expressions, interactions, and clinical implications of leukemia inhibitory factor (LIF) in human reproduction. DESIGN: Review of published articles. SETTING: Clinical development unit of biotechnology company. INTERVENTION(S): None. RESULT(S): In the endometrium, LIF is expressed in a menstrual cycle-dependent manner, with the highest level occurring at the time of implantation. LIF is also detected in uterine flushing, and its level is significantly lower in women with unexplained infertility. Likewise, endometrial explants derived from women with unexplained infertility showed reduced levels of LIF secretion. Binding of LIF to LIF receptor and gp130 activates signal transduction pathways. LIF receptor is expressed in endometrium, oocytes, and blastocysts. Cytotrophoblasts cultured in the presence of LIF differentiate toward an anchoring extravillous phenotype. CONCLUSION(S): On the basis of reports gathered from animal and human studies, LIF appears to play an important role in implantation and in the establishment of pregnancy.

Safety, pharmacokinetics and pharmacodynamics of recombinant human tumour necrosis factor-binding protein-1 (Onercept) injected by intravenous, intramuscular and subcutaneous routes into healthy volunteers.

The safety, pharmacokinetics and pharmacodynamics of recombinant human tumour necrosis factor-binding protein-1 (r-hTBP-1, Onercept) were investigated after intravascular and extravascular injection, in three studies in healthy volunteers. Subjects received Onercept as single intravenous doses of 5, 15, 50 and 150 mg, or single IV, IM, SC injection of 50 mg, or six repeated SC injections of 50 mg. Based on vital signs, hematology and blood chemistry, antibodies to study drug and local tolerability, r-hTBP-1 exhibited a remarkably safe profile. There was no evidence of alteration of hepatic oxidative metabolism. Recombinant-hTBP-1 showed linear pharmacokinetics that could be described by a triexponential model, and exhibited an initial half-life of 30 min, an intermediate half-life of 4 hours and a terminal elimination half-life of about 15 hours, although it was prolonged to 21 hours after repeated SC injections. The total clearance was estimated at 4 l/h. The initial (Vc) and steady state (Vss) volumes of distribution were approximately 4 l and 10 l, respectively. Renal clearance was minimal, representing around 2.5% of the total clearance, and remained constant after increasing doses of r-hTBP-1. The absorption was slow and biphasic. The immunoactivity of r-hTBP-1 was closely related to its biological activity, although the assessment was limited to only some of the samples. As anticipated in normal healthy volunteers, the pharmacodynamic response was generally not different from placebo. Total TNF-alpha serum levels increased slightly, 1 hour following IV administration of 50 mg and 150 mg r-hTBP-1. However, no major increase in the active entity levels (free TNF-alpha) was observed. In addition, no TNF-alpha-driven biological response was observed, i.e. C-reactive protein, IL-6 and fibrinogen remained almost constant, as did transferrin and albumin. Its safety profile and pharmacokinetic characteristics make Onercept a candidate drug suitable for antagonising pathologically high levels of TNF-alpha as reported in inflammatory, immune and cardiovascular diseases.

Pharmacokinetics and pharmacodynamics of IFN-beta 1a in healthy volunteers.

The pharmacokinetics of recombinant human interferon-beta1a (IFN-beta1a) (Rebif, Ares-Serono, Geneva, Switzerland) were investigated in healthy volunteers following intravenous (i.v.) administration of increasing single doses of the drug (22 microg/6 million international units [MIU], 44 microg/12 MIU, and 66 microg/18 MIU); i.v., intramuscular (i.m.), and subcutaneous (s.c.) administration of a 66-microg dose; and repeated s.c. administration of four 66-microg doses at 48-h intervals. The disposition of IFN-beta1a followed triexponential decay after i.v. administration (half-lives 3 min, 42 min, and 22 h, respectively). After s.c. and i. m. administration, absorption was the rate-limiting factor in the terminal phase. The median absolute bioavailabilities were 30% and 27%, respectively. The accumulation ratio after repeated s.c. injections was 2.4, and a terminal half-life of 66 h was observed. Intracellular 2-5A synthetase activity and serum neopterin and beta2-microglobulin concentrations increased after all IFN-beta1a injections and remained elevated following every-other-day administration. The local tolerance was good, and the systemic tolerance was satisfactory.

Influence of interferon beta-1a dose frequency on PBMC cytokine secretion and biological effect markers.

Interferon-beta regimens for immune-mediated diseases, such as multiple sclerosis (MS), have not been compared regarding their biological effects. In this randomized, parallel-group, placebo-controlled study, cytokine secretion by mitogen-stimulated PBMCs and serum response markers were assessed in volunteers receiving subcutaneous recombinant IFN beta-1a (Rebif, Ares-Serono) 22 microg once a week (QW), 22 microg three times a week, 66 microg QW, or placebo. The production of IL-1beta, IL-6, IFN-gamma, TNF-alpha and TNF-beta markedly decreased during 24-48 h after each injection, with limited dose-dependency and no evidence of tolerance or effect augmentation over 1 month. IL-10 secretion remained unchanged. The increase in serum beta2-microglobulin, neopterin and 2-5A-synthetase was more sustained. Thus, IFN-beta-induced immunomodulation in vivo strongly depends on the administration schedule, the time-integrated effect being 2-3 times greater when a same weekly dose is divided in three injections.

Down-regulation models and modeling of testosterone production induced by recombinant human choriogonadotropin.

Chorionic gonadotropin (CG) is a glycoprotein hormone, whose action is mediated by the luteinizing hormone/CG receptor. Testosterone concentrations from six pituitary-desensitized, healthy male volunteers were obtained after four different administrations of recombinant-human CG (rhCG). We present a modeling study to provide a possible explanation for the observations that increased exposure to rhCG induces higher and then lower testosterone concentrations and that marked rebound effects are observed at the end of repeated administration of rhCG. We used semimechanistic models (in which flexible functions represent unknown parts of the models) to identify the relationship of rhCG concentrations to the testosterone levels. Based on the results obtained with the semimechanistic models, different mechanistic down-regulation models were devised and tested. The final model uses a one-compartment model to describe the endogenous production rate of testosterone; rhCG affects the production rate with a mechanism consistent with a two-site binding site, with effect proportional to one-site bound concentration. The modeling results indicate that when rhCG concentration increases, the testosterone production rate increases to 45 times the baseline value. However, at an rhCG concentration of more than about 30 IU/liter, the production rate decreases. Simulations showed that both dose and dosing interval profoundly influence testosterone response to rhCG.

The population pharmacokinetics of recombinant- and urinary-human follicle stimulating hormone in women.

AIMS: To characterize the pharmacokinetics of recombinant-human follicle stimulating hormone (r-hFSH) and urinary-human follicle stimulating hormone (u-hFSH) using population pharmacokinetic analysis and deconvolution techniques. METHODS: Sparse data were available from 62 female patients who received u-hFSH intramuscularly (i.m.) and 60 female patients who received r-hFSH subcutaneously (s.c.) as part of an in vitro fertilisation and embryo transfer (IVF-ET) procedure. The dose of u-hFSH and r-hFSH was 225 International Units (IU) FSH/day for the first 5 days of treatment. The dose of u-hFSH/r-hFSH on subsequent days depended upon the ovarian response. Intensively sampled data were also available from 12 female volunteers who received r-hFSH, 150 IU, on three occasions: intravenously (i.v.), i.m. and s.c., each separated by 1 week of wash-out. The volunteers then received multiple r-hFSH doses by the s.c. route: 150 IU once daily for 7 days. Intensively sampled data were available from a further 12 female volunteers who received u-hFSH, 150 IU, given by the i.v. and i.m. routes. RESULTS: Analysis of the intensively sampled r-hFSH and u-hFSH data sets found that disposition could be described using a two-compartment model and that absorption was rate limiting and essentially a first order process, for both compounds. The population estimate of clearance (CL) after i.v. administration was 0.60 and 0.44 l h(-1) for r-hFSH and u-hFSH respectively. The calculated mean residence times (MRT) for r-hFSH and u-hFSH were 16 and 18 h, respectively. The different bioavailabilities (F) and mean absorption times (MAT) determined after i.m. and s.c. administration ranged from 0.60 to 0.77 and from 27 h to 48 h, depending on compound, administration route, data type and method of analysis. Population analysis of the sparse patient data found that a one compartment model with first order absorption was adequate to describe the r-hFSH and u-hFSH data. The population estimates of apparent clearance (CL/F) were 0.71 and 0.33 l h(-1) for r-hFSH and u-hFSH respectively. Urinary-hFSH CL/F increased linearly with weight and was 0.33 l h(-1) at the average weight of 58.5 kg. No other covariates (age, weight, height, creatinine clearance, body mass index, race) were found to influence the FSH disposition parameters. The sparse data population estimates of intersubject variability in CL/F for r-hFSH and u-hFSH were essentially the same, 26% and 25%, respectively. CONCLUSIONS: The population analysis indicates that the variability in CL/F is moderate, consequently, so would be the variability in exposure, given a fixed dosage regimen.

Clinical pharmacology of recombinant human luteinizing hormone: Part I. Pharmacokinetics after intravenous administration to healthy female volunteers and comparison with urinary human luteinizing hormone.

OBJECTIVE: To assess the pharmacokinetics after i.v. administration of a recombinant human LH and to compare them to those of a reference hMG preparation containing urinary human LH. DESIGN: Prospective, dose-escalating, cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received single i.v. doses of 300, 10,000, and 40,000 IU of recombinant human LH, followed by a single i.v. dose of 300 IU of hMG, all separated by 1 week. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters. RESULTS: For both preparations, LH serum levels were well described by similar biexponential models. The pharmacokinetics of recombinant human LH were linear over the 300 to 40,000 IU range. After a rapid distribution phase with an initial half-life of 1 hour, both recombinant human LH and urinary human LH were eliminated with a terminal half-life of 10-12 hours. Total serum clearance was 1.7 L/h with < 4% and 30% of the dose being eliminated in the urine for recombinant human LH and urinary human LH, respectively. The volume of distribution at steady-state was approximately 10 L. Irrespective of the dose, recombinant human LH was well tolerated. CONCLUSION(S): The pharmacokinetics of recombinant human LH are linear with dose and similar to those of urinary human LH.

Clinical pharmacology of recombinant human luteinizing hormone: Part II. Bioavailability of recombinant human luteinizing hormone assessed with an immunoassay and an in vitro bioassay.

OBJECTIVE: To assess the single-dose pharmacokinetics of a recombinant human LH preparation administered by the i.v., i.m., and s.c. route. DESIGN: Prospective, randomized cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received single i.v., i.m., and s.c. doses of 10,000 IU of recombinant human LH, each separated by 1 week. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters. RESULT(S): After single i.v. administration, the pharmacokinetics were described by a two-compartment model, after i.m. or s.c. administration, by a one-compartment model with zero order absorption and a lag time. Using the immunoassay, after i.v. administration initial half-life was 1 hour and terminal half-life was 10 hours (half-life was prolonged after extravascular administration, suggesting rate-limiting absorption). Total serum clearance was 2.6 L/h, and steady, state volume of distribution was 14 L. Observed Cmax, after i.m. and s.c. administration, was 43 IU/L with median tmax of 9 hours (i.m.) and 5 hours (s.c.). Bioavailability was 0.54 (i.m.) and 0.56 (s.c.). The pharmacokinetics of LH are comparable using an in vitro bioassay. CONCLUSION(S): The terminal half-life of recombinant human LH is around 12 hours and is slightly prolonged after extravascular administration. The pharmacokinetics are similar after i.m. and s.c. injection, and one-half the administered dose is available systemically.

Pharmacokinetic and pharmacodynamic interactions between recombinant human luteinizing hormone and recombinant human follicle-stimulating hormone.

OBJECTIVE: To assess the pharmacokinetics of a recombinant human LH preparation and its pharmacokinetic and pharmacodynamic interactions with recombinant human follicle-stimulating hormone (FSH). DESIGN: Prospective, randomized cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received 150 IU of s.c. recombinant human LH and FSH, either alone or in combination, followed by recombinant human LH and FSH once daily for 7 days. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters, ovarian follicle development. RESULT(S): No pharmacokinetic interaction between recombinant human LH and FSH was observed, with no significant difference in baseline-corrected maximal observed concentration over baseline, area under the concentration-time curve from t = 0 to t = 24 hours, or time to maximal concentration after single doses alone or in combination. After daily administration, the mean accumulation ratio was 1.6 for LH and 2.9 for FSH, with absorption and terminal phase half-life estimates of 4 and 11 hours for LH and 8 and 16 hours for FSH, respectively. Combined administration of FSH and LH for 7 days was effective in stimulating ovarian follicular development and steroidogenesis, with large interindividual variability related to ovarian sensitivity. CONCLUSION(S): A new recombinant human LH preparation has a low accumulation ratio at steady-state and no pharmacokinetic or pharmacodynamic interactions with recombinant human FSH.