Population pharmacokinetic modelling of irosustat in postmenopausal women with oestrogen-receptor positive breast cancer incorporating non-linear red blood cell uptake.

PURPOSE: Irosustat is the 'first-in-class' irreversible potent steroid sulphatase inhibitor with lack of oestrogenic activity. The objective of this work was to develop a population model characterizing simultaneously the pharmacokinetic profiles of irosustat in plasma and whole blood. METHODS: This clinical study was an open label, multicentre, phase I multiple cohort dose escalation trial conducted in 35 postmenopausal women with oestrogen-receptor positive breast cancer. Patients received 1, 5, 20, 40, or 80 mg oral doses. Irosustat was administered as a single oral dose to each patient followed by an observation period of 7 days. On day 8 each patient received once daily oral administration until day 34. Concentrations of irosustat in both blood and plasma were obtained and pharmacokinetic analyses were performed with NONMEM 7.2. RESULTS AND CONCLUSIONS: Irosustat showed non-linear disposition characteristics modelled as maximum binding capacity into the red blood cells. Plasma concentration corresponding to half of the maximum capacity was 32.79 ng/mL. The value of the blood to plasma concentration ratio in linear conditions was 419, indicating very high affinity for the red blood cells. Apparent plasma and blood clearances were estimated in 1199.52 and 3.90 L/day, respectively. Pharmacokinetics of irosustat showed low-moderate inter-subject variability, and neither the demographics (e.g., age, or weight) nor the phenotypes for CYP2C9, CYP2C19, and CYP3A5 enzymes showed statistically significant effects. Relative bioavailability was decreased as the administered dose was augmented. The model predicted a 47% decrease in relative bioavailability in the 40 mg with respect to the 1 mg dose.

Transbuccal delivery of doxepin: studies on permeation and histological investigation.

According to previous studies reporting the anesthetic/analgesic action of oral topical doxepin administration, this study evaluated a model of buccal permeation to determine the depth of delivery of doxepin into excised porcine buccal mucosa following topical application of a saturated aqueous doxepin solution. Buccal mucosa permeation studies were performed using Franz diffusion cells. Cumulative amounts of doxepin permeated were plotted as a function of time. Kinetic permeation parameters as flux (Js), lag time (Tl) and permeability coefficient (Kp) were calculated. Theoretical human plasmatic steady-state doxepin concentration and drug retained in the tissue were also determined in order to evaluate its potential therapeutic use, central or peripheral. Finally, a histological evaluation of the buccal mucosa was performed to test potential damage due to the permeation phenomenon. Obtained results showed a poor aqueous doxepin permeation through buccal mucosa membrane (median parameters Js=34.79 µg/h, Kp=0.49×10(-3)cm/h and Tl=2.8h). Predicted doxepin plasma concentrations would reach 46 ng/mL, far from the required to have central nervous system activity as tricyclic agent. However, median doxepin amount remaining in the mucosa membrane was 0.24 µg/cm(2)/µg tissue, which evidenced a reservoir function of the buccal mucosa. Histologically, no structural damage was observed in the tissues. This study lays the foundation for further research within this area with a view to potentially adopting alternative strategies for enhanced buccal absorption of doxepin in clinical practice.

A phase I dose escalation study to determine the optimal biological dose of irosustat, an oral steroid sulfatase inhibitor, in postmenopausal women with estrogen receptor-positive breast cancer.

Steroid sulfatase (STS) inhibition may have a therapeutic role in suppression of endocrine-responsive breast cancer. This study aimed to determine the optimal biological dose and recommended dose (RD) of the STS inhibitor irosustat. A three-part, open-label, multicenter, dose escalation study of irosustat in estrogen receptor-positive breast cancer patients involved administration of a single dose of irosustat with a 7-day observation period; followed by a daily oral dose of irosustat for 28 days; and an extension phase, in which the daily oral dose of irosustat was continued at the discretion of the investigator and as long as the patient was benefitting from the treatment. Five doses of irosustat were tested (1, 5, 20, 40, and 80 mg) in 50 patients. After 28 days of daily administration of irosustat, all the evaluated patients in the 5, 20, 40, and 80 mg cohorts achieved ≥95 % STS inhibition in peripheral blood mononuclear cells and corresponding endocrine suppression. The maximum tolerated dose was not reached, and the 40 mg dose was established as the RD. The median time to disease progression in the 40 mg cohort was 11.2 weeks. Disease stabilization was achieved in 10 % of patients potentially indicative of drug activity. Dry skin was the most frequent adverse event. The RD of irosustat is 40 mg. Disease stabilization occurred in 10 % of this heavily pretreated patient population. A larger study is required to define an accurate response rate to irosustat as a single agent and whether co-administration with an aromatase inhibitor is needed.

Skin permeation of cacalol, cacalone and 6-epi-cacalone sesquiterpenes from a nanoemulsion.

The objective of the present study was to investigate the transdermal permeation of cacalol (1) and a mixture of cacalone (2) and 6-epi-cacalone (3) in comparison with diclofenac acid (4) delivered from the same characterized nanoemulsion using Franz diffusion cells (formulae I, II and III). Results show that de Kp, J, Q24, PI and P2 were higher for the acid diclofenac nanoemulsion than for the natural products nanoemulsions. As for the differences between the formulations I and II, with the natural products, Q24, the quantity extracted from skin and P2 were higher in the mixture of 2 and 3 nanoemulsion compared with the corresponding nanoemulsion of 1. In conclusion, the low permeability of the natural products nanoemulsions in comparison with that of diclofenac acid has the potential for development for drugs with local and systemic applications, respectively.

Pharmacokinetic/pharmacodynamic model of the testosterone effects of triptorelin administered in sustained release formulations in patients with prostate cancer.

The objectives of the current work were to develop a predictive population pharmacokinetic (PK)/pharmacodynamic (PD) model for the testosterone (TST) effects of triptorelin (TRP) administered in sustained-release (SR) formulations to patients with prostate cancer and determine the minimal required triptorelin serum concentration (C(TRP_min)) to keep the testosterone levels of the patients below or equal to the level of castration (TST ≤ 0.5 ng/ml). A total of eight healthy male volunteers and 74 patients with prostate cancer received one or two doses of triptorelin injected subcutaneously or intramuscularly. Five different triptorelin formulations were tested. Pharmacokinetic (serum concentration of triptorelin) and pharmacodynamic (TST levels in serum) data were analyzed by using the population approach with NONMEM software (http://www.iconplc.com/technology/products/nonmem/). The PK/PD model was constructed by assembling the agonist nature of triptorelin with the competitive reversible receptor binding interaction with the endogenous agonist, a process responsible for the initial and transient TST flare-up, and triggering down-regulation mechanisms described as a decrease in receptor synthesis. The typical population values of K(D), the receptor equilibrium dissociation constant of triptorelin, and C(TRP_min) to keep 95% of the patients castrated were 0.931 and 0.0609 ng/ml, respectively. The semimechanistic nature of the model renders the predictions of the effect of triptorelin on TST possible regardless the type of SR formulation administered, while exploring different designs during the development of new delivery systems.

Population pharmacokinetic/pharmacodynamic modeling of drug-induced adverse effects of a novel homocamptothecin analog, elomotecan (BN80927), in a Phase I dose finding study in patients with advanced solid tumors.

PURPOSE: To characterize the pharmacokinetic profile of elomotecan, a novel homocamptothecin analog, evaluate the dose-limiting toxicities, and establish the relationship between exposure and toxicity in the first Phase I study in patients with advanced malignant solid tumors. Preliminary antitumor efficacy results are also provided. DESIGN: Elomotecan was administered as a 30-min intravenous infusion at doses ranging from 1.5 to 75 mg once every 3 weeks to 56 patients with advanced solid tumors. Plasma concentration data and adverse effects were modeled using the population approach. RESULTS: Elomotecan showed linear pharmacokinetics, and clearance was decreased with age. The model predicts a 47 and 61 % reduction in CL for patients aged 60 and 80 years, respectively, when compared with younger patients (30 years). Neutropenia represented the dose-limiting toxicity. The maximum tolerated dose and the recommended dose (RD) were 75 and 60 mg, respectively. Elomotecan elicited a 20, 5, 2, and 2 % severe (grade 4) neutropenia, asthenia, nausea, and vomiting at the RD, respectively. Of the subjects in the RD cohort, 41.7 % had a stable disease mean duration of 123.6 ± 43.4 days. CONCLUSIONS: The pharmacokinetic parameters and the toxicity pattern of elomotecan suggest that this novel homocamptothecin analog should be further explored in the clinical setting using a dose of 60 mg administered as a 30-min intravenous infusion, once every 3 weeks.

In vitro evaluation of the interaction potential of irosustat with drug-metabolizing enzymes.

Irosustat is a first-generation, irreversible, steroid sulfatase inhibitor currently in development for hormone-dependent cancer therapy. To predict clinical drug-drug interactions between irosustat and possible concomitantly administered medications, the inhibition/induction potential of irosustat with the main drug-metabolizing enzymes was investigated in vitro. The interaction of aromatase inhibitors in the in vitro metabolism of irosustat was also studied. Irosustat inhibited CYP1A2 activity in human liver microsomes through the formation of its desulfamoylated degradation product and metabolite 667-coumarin. CYP1A2 inhibition by 667-coumarin was competitive, with a K(i) of 0.77 µM, a concentration exceeding by only 5-fold the maximal steady-state concentration of 667-coumarin in human plasma with the recommended dose of irosustat. In addition, 667-coumarin metabolites enhanced the inhibition of CYP1A2 activity. Additional clinical interaction studies of irosustat with CYP1A2 substrate drugs are strongly recommended. 667-Coumarin also appeared to be a competitive inhibitor of CYP2C19 (K(i) = 5.8 µM) in human liver microsomes, and this inhibition increased with assessment in human hepatocytes. Inhibition of CYP2C19 enzyme activity was not caused by repression of CYP2C19 gene expression. Therefore, additional mechanistic experiments or follow-up studies with clinical evaluation are recommended. Irosustat neither inhibited CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2D6, CYP2E1, CYP3A4/5, or UDP-glucuronosyltransferase 1A1, 1A4, or 2B7 activities nor induced CYP1A2, CYP2C9, CYP2C19, or CYP3A4/5 at clinically relevant concentrations. Results from human liver microsomes indicated that no changes in irosustat pharmacokinetics in vivo are expected as a result of inhibition of irosustat metabolism in cases of concomitant medication administration or irosustat-aromatase inhibitor combination therapy with letrozole, anastrozole, or exemestane.

Pharmacodynamic modeling of the effects of lanreotide Autogel on growth hormone and insulin-like growth factor 1.

Acromegaly arises from excessive levels of growth hormone (GH), many of whose effects are mediated by stimulation of secretion of insulin-like growth factor 1 (IGF-1). Synthetic somatostatin analogues inhibit GH secretion. The objective of the study was to develop a population pharmacodynamic model describing the relationship between serum concentrations of lanreotide (C(P)) and its GH and IGF-1 effects in patients with acromegaly receiving lanreotide Autogel (LA) at doses of 60, 90, or 120 mg by deep subcutaneous route every 28 days. Data were analyzed from 104 patients. The GH and IGF-1 profiles were fit simultaneously using the population approach with NONMEM. The GH vs C(P) and the IGF-1 vs GH relationships were described using inhibitory I(max) and E(max) models, respectively. Results indicated that lanreotide cannot abolish GH completely. C(P) levels of 3.4 ng/mL are required to achieve percentages of hormonal control (GH and IGF-1) of 21% and 36% in not treated and previously treated patients. If the focus is only GH, a C(P) of 3.4 ng/mL corresponds to 33% and 56% controlling rates. Simulations showed that there is a possible clinical benefit if the highest dose of 120 mg LA is administered to patients who are not well controlled by lower doses of LA.

Drug interaction potential of toremifene and N-desmethyltoremifene with multiple cytochrome P450 isoforms.

Toremifene is an effective agent for the treatment of breast cancer in postmenopausal women and is being evaluated for its ability to prevent bone fractures in men with prostate cancer taking androgen deprivation therapy. Due to the potential for drug-drug interactions, the ability of toremifene and its primary circulating metabolite N-desmethyltoremifene (NDMT) to inhibit nine human cytochrome P450 (CYP) enzymes was determined using human liver microsomes. Induction of CYP1A2 and 3A4 by toremifene was also investigated in human hepatocytes. Toremifene did not significantly inhibit CYP1A2 or 2D6. However, toremifene is a competitive inhibitor of CYP3A4, non-competitive inhibitor of CYP2A6, 2C8, 2C9, 2C19 and 2E1 and mixed-type inhibitor of CYP2B6. CYP inhibition by NDMT was similar in magnitude to toremifene. Toremifene did not induce CYP1A2 but increased CYP3A4 monooxygenase activity and gene expression in drug-exposed human primary hepatocytes. Although clinical doses of toremifene produce steady state exposures to toremifene and NDMT that may be sufficient to cause pharmacokinetic drug-drug interactions with other drugs metabolised by CYP2B6, CYP2C8, CYP3A4, CYP2C9 and CYP2C19, these data indicate that toremifene is unlikely to play a role in clinical drug-drug interactions with substrate drugs of CYP1A2 and CYP2D6.

In vitro metabolism of irosustat, a novel steroid sulfatase inhibitor: interspecies comparison, metabolite identification, and metabolic enzyme identification.

Irosustat is a novel steroid sulfatase inhibitor for hormone-dependent cancer therapy. Its structure is a tricyclic coumarin-based sulfamate that undergoes desulfamoylation in aqueous solution, yielding the sulfamoyl-free derivative, 667-coumarin. The aim of the present work was to study the in vitro metabolism of irosustat, including its metabolic profile in liver microsomes and hepatocytes, the potential species differences, and the identification of the main metabolites and of the enzymes participating in its metabolism. Irosustat was extensively metabolized in vitro, showing similar metabolite profiles among rat, dog, monkey, and humans (both sexes). In liver microsomes, the dog was the species that metabolized irosustat most similarly to metabolism in humans. Marked differences were found between liver microsomes and hepatocytes, meaning that phase I and phase II enzymes contribute to irosustat metabolism. Various monohydroxylated metabolites of irosustat and of 667-coumarin were found in liver microsomes, which mostly involved hydroxylations at the C8, C10, and C12 positions in the cycloheptane ring moiety. 667-Coumarin was formed by degradation but also by non-NADPH-dependent enzymatic hydrolysis, probably catalyzed by microsomal steroid sulfatase. The main metabolites formed by hepatocytes were glucuronide and sulfate conjugates of 667-coumarin and of some of its monohydroxylated metabolites. The major cytochrome P450 enzymes involved in the transformation of irosustat were CYP2C8, CYP2C9, CYP3A4/5, and CYP2E1. Moreover, various phase II enzymes (UDP-glucuronosyltransferases and sulfotransferases) were capable of conjugating many of the metabolites of irosustat and 667-coumarin; however, the clinically relevant isoforms could not be elucidated.

Predictive ability of a semi-mechanistic model for neutropenia in the development of novel anti-cancer agents: two case studies.

In cancer chemotherapy neutropenia is a common dose-limiting toxicity. An ability to predict the neutropenic effects of cytotoxic agents based on proposed trial designs and models conditioned on previous studies would be valuable. The aim of this study was to evaluate the ability of a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model for myelosuppression to predict the neutropenia observed in Phase I clinical studies, based on parameter estimates obtained from prior trials. Pharmacokinetic and neutropenia data from 5 clinical trials for diflomotecan and from 4 clinical trials for indisulam were used. Data were analyzed and simulations were performed using the population approach with NONMEM VI. Parameter sets were estimated under the following scenarios: (a) data from each trial independently, (b) pooled data from all clinical trials and (c) pooled data from trials performed before the tested trial. Model performance in each of the scenarios was evaluated by means of predictive (visual and numerical) checks. The semi-mechanistic PK/PD model for neutropenia showed adequate predictive ability for both anti-cancer agents. For diflomotecan, similar predictions were obtained for the three scenarios. For indisulam predictions were better when based on data from the specific study, however when the model parameters were conditioned on data from trials performed prior to a specific study, similar predictions of the drug related-neutropenia profiles and descriptors were obtained as when all data were used. This work provides further indication that modeling and simulation tools can be applied in the early stages of drug development to optimize future trials.

Population pharmacokinetics of high-dose methotrexate after intravenous administration in pediatric patients with osteosarcoma.

The goal of this study was to establish the population pharmacokinetics (PK) of high-dose methotrexate (HD-MTX) treatment in children with osteosarcoma and to explore the influence of patient covariates and between-occasion variability on drug disposition. Patient covariates and concentration-time data were collected. PK data analysis from 209 HD-MTX cycles from 14 patients was performed using the population approach (NONMEM V). Internal and external validations were performed to confirm the model. PK of methotrexate was best described by a 2-compartment open PK model with first-order elimination from the central compartment. Between-subject variability (BSV) was included in total plasma clearance (CL) and in central compartment distribution volume (V1) [coefficient of variation (CV) 11.9% and 8.9%, respectively]. The CV of BSV in the residual error was 25.5%. Between-occasion variability was only retained for CL (CV 8.2%). RE consisted of a proportional error of 41.6%. Age and body weight in CL and body weight in V1 were identified as the appropriate covariates. The final estimates of total CL and V1 were given by the equations CL = 88.5.(AGE/15) + 27.4 x (WGT/50) L/d and V1 = 11.0 + 5.6 x (WGT/50) L, respectively. Internal validation results showed that the 95% confidence interval covered all the observed MTX concentrations. Mean bias and precision of the individual predicted concentrations, calculated in a validation dataset, resulted in -1.36% and 19.71%, respectively. A population PK model was developed for HD-MTX in children with osteosarcoma. Validation studies confirmed the suitability of the model for further dose individualization by means of a Bayesian approach.

Population pharmacokinetic analysis of lanreotide Autogel in healthy subjects : evidence for injection interval of up to 2 months.

BACKGROUND AND OBJECTIVE: Lanreotide is a somatostatin analogue used for the treatment of acromegaly and neuroendocrine tumours. The objective of this study was to develop a pharmacokinetic model for the sustained-release formulation lanreotide Autogel after deep subcutaneous administration in healthy subjects, and to explore the potential effect of covariates, especially sex and dose. SUBJECTS AND METHODS: This was an open-label, single-centre, randomized, dose-ranging, parallel-group study, with a follow-up period of 4-7 months following drug administration in healthy subjects. Healthy Caucasian subjects aged 18-45 years were included. Subjects received a rapid intravenous bolus of 7 microg/kg of an immediate-release formulation of lanreotide (lanreotide IRF). After a 3-day washout period, participants were randomized to receive a single deep subcutaneous injection of lanreotide Autogel at a dose of 60, 90 or 120 mg. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Blood samples for lanreotide determination were obtained during the first 12 hours after the intravenous bolus injection and during the 4- to 7-month follow-up period after deep subcutaneous administration of lanreotide Autogel. Data after intravenous and subcutaneous administration were fitted simultaneously using the population approach in NONMEM((R)) version VI software. The model was validated externally using data from patients with acromegaly. RESULTS: In total, 50 healthy subjects (24 women and 26 men) received a single intravenous dose of lanreotide IRF. Of these, 38 subjects (18 women and 20 men) received a single subcutaneous dose of lanreotide Autogel 3 days after intravenous lanreotide IRF. The disposition of lanreotide was described by a three-compartment open model. The estimates of the total volume of distribution and serum clearance were 15.1 L and 23.1 L/h, respectively. The estimates of interindividual variability were <40%. To evaluate lanreotide Autogel pharmacokinetics, the absorption rate was modelled to decrease exponentially as a function of the natural logarithm of time. The absolute bioavailability after deep subcutaneous administration of lanreotide Autogel was 63%. The rate of absorption and bioavailability of lanreotide Autogel were independent of the administered dose in the range from 60 to 120 mg, and no significant effect of covariates (sex, dose, age or bodyweight) was found (p > 0.05). CONCLUSIONS: Population analysis allows a full description of the disposition of lanreotide after rapid intravenous bolus administration of lanreotide IRF (7 microg/kg) and the pharmacokinetics of lanreotide Autogel after a single deep subcutaneous injection (60, 90 or 120 mg) in healthy subjects. The model-based simulations provide support for the feasibility of extending the dosing interval for lanreotide Autogel to 56 days when given at 120 mg. The absorption profile of lanreotide Autogel was independent of the dose and was not affected by sex.

Pharmacokinetic profile of the somatostatin analogue lanreotide in individuals with chronic hepatic insufficiency.

BACKGROUND AND OBJECTIVES: The somatostatin analogue lanreotide is indicated for the treatment of acromegaly and to relieve the symptoms of neuroendocrine tumours. The objective of the present study was to compare the pharmacokinetic profile and safety of intravenous lanreotide in healthy volunteers and individuals with hepatic impairment. METHODS: Immediate-release lanreotide was administered at 7 microg/kg during a 20-minute intravenous infusion. Blood samples were collected over 24 hours and lanreotide serum levels determined by radioimmunoassay. Pharmacokinetic parameters were estimated by non-compartmental analyses. RESULTS: Two study centres recruited 53 individuals. Study A comprised 10 individuals with hepatic insufficiency Child-Pugh grade A (mild), 7 with grade B (moderate) and 12 healthy volunteers - all Caucasian. Study B comprised 4 individuals with hepatic insufficiency Child-Pugh grade A, 6 with grade B, 2 with grade C (severe) and 12 healthy volunteers - all Chinese. All participants were included in the safety analysis. The pharmacokinetic analysis included all participants from study B, but only 12 with hepatic impairment and 11 healthy volunteers from study A. Combined analysis of both studies showed an increased serum elimination half-life (57%; p < or = 0.001), mean residence time (53%; p < or = 0.001) and volume of distribution (at steady state, 57%; at terminal disposition phase, 64%; both p < or = 0.001) in individuals with mild hepatic insufficiency compared with healthy volunteers. These differences were more pronounced in individuals with moderate-to-severe hepatic insufficiency compared with healthy volunteers; additionally, the area under the serum concentration-time curve from time zero to infinity (AUC(infinity)) was increased (23%; p < or = 0.05) and clearance (CL) decreased (19%; p < or = 0.05) compared with healthy volunteers. The peak serum concentration of lanreotide tended to be lower in individuals with hepatic insufficiency than in healthy volunteers (statistically non-significant). There were no pharmacokinetic differences between the two groups of healthy volunteers. Lanreotide was well tolerated with only two mild adverse events that were considered to be possibly related to treatment (both nausea and headache with either vomiting or dizziness). There were no clinically relevant changes in laboratory parameters or vital signs during the study. CONCLUSION: The pharmacokinetic profile of lanreotide depends on the severity of hepatic insufficiency with CL and AUC(infinity), which are only slightly altered with moderate-to-severe insufficiency. The changes in exposure do not, however, require dosage adjustment. Moreover, lanreotide is usually given as a prolonged-release microparticle or Autogel formulation, and terminal half-life and serum concentrations depend on the release properties of the formulation. Dosing is also adapted for each patient, based on therapeutic response. Thus, hepatic insufficiency does not require additional dosage adjustments.

Phase I dose-finding study and a pharmacokinetic/pharmacodynamic analysis of the neutropenic response of intravenous diflomotecan in patients with advanced malignant tumours.

PURPOSE: To determine the maximum tolerated dose (MTD) of intravenous (iv) diflomotecan administered once every 3 weeks, and to characterize the relationship between pharmacokinetics and neutropenic effect, using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. EXPERIMENTAL DESIGN: Twenty-four patients received a total of 75 cycles of iv diflomotecan that was administered as 20-min infusion, once every 3 weeks at escalating doses of 2, 4, 5, and 6 mg/m2. Haematological and non-haematological toxicities were evaluated. Plasma concentrations of diflomotecan were measured after the first drug administration. RESULTS: Dose limiting toxicity (DLT) following the first cycle occurred in 12 patients and a total of 16 patients experienced DLT at some point in the trial. During the first cycle of treatment the number of patients in the 5 and 6 mg/m2 dose groups that experienced DLT was 3 of 4, and 3 of 3, respectively. Therefore, the dose of 5 mg/m2 was considered the MTD and the dose of 4 mg/m2 the recommended dose (RD). During the first cycle, 12 patients experienced DLT, six had either infection of haematological toxicity and eight complained of fatigue. The best response was a partial response in one patient treated at the 6 mg/m2 dose level. Disease stabilization was observed in seven patients (four patients treated at 4 mg/m2 and one patient at each dose level of 2, 5, and 6 mg/m2). The remaining patients had all progressive disease. The median time to progression for all patients was 5.9 weeks. Pharmacokinetics of diflomotecan was described with a three-compartmental model. Mean population parameter estimates of the apparent volume of distribution of the central compartment (V c) increased linearly with body surface area (BSA) as: V c (L) = 41.5 x (BSA/1.85), and the mean population estimate of the apparent volume of distribution of the shallow compartment was lower in females (29.5 vs 48.8 L). Computer simulations showed the lack of clinical significance of these covariates. The time course of the neutropenic response was adequately described by a semi-mechanistic model that includes cellular processes and drug effects. CONCLUSIONS: The MTD and RD after a 20-min iv infusion of diflomotecan every 3 weeks are 4 and 5 mg/m2, respectively. Diflomotecan showed linear pharmacokinetic behaviour and the selected PK/PD model described adequately the time course of neutropenia. The mean model predicted values of nadir and time to nadir after a 20-min iv infusion of 4 mg/m2 of diflomotecan was 0.86 x 10(9) /L neutrophil cell counts and 11 days, respectively.

Pharmacokinetics and population pharmacodynamic analysis of lanreotide Autogel.

Somatostatin analogs are the first-line medical therapy for acromegaly, and the treatment of this disease has been simplified by the development of extended-release formulations of these analogs. Lanreotide is a somatostatin analog that is available either as the microparticle formulation, requiring 7- to 14-day dosing, or as the aqueous Autogel formulation, requiring 28-day dosing. This study investigated the pharmacokinetics and pharmacodynamics of lanreotide. Patients with acromegaly were given 5 injections of lanreotide microparticles, 30 mg, followed by 3 injections of lanreotide Autogel, at doses of 60, 90, or 120 mg every 28 days. The study was extended to a further 12 injections of lanreotide Autogel with dose titration. A total of 144 patients were recruited; 130 received 3 injections of lanreotide Autogel, and 130 completed the extension phase. Average minimum lanreotide concentrations (Cmin) at steady state were 1.949 +/- 0.619, 2.685 +/- 0.783, and 3.575 +/- 1.271 ng/mL for 60, 90, and 120 mg of lanreotide Autogel, respectively, showing a dose-proportional increase. Population pharmacodynamic analysis showed that the relationship between either formulation of lanreotide and serum growth hormone (GH) concentrations was best described using an inhibitory maximum response (Emax) model that allowed for the possibility of an incomplete inhibition of GH. Lanreotide elicited a maximum reduction in GH of 82%. Because patients were already being treated, baseline GH (E0) was estimated, and the value of 8.63 ng/mL was in agreement with the inclusion criteria of GH 10 ng/mL or less. The effectiveness of treatment was demonstrated by the median serum concentration of lanreotide, 1.13 ng/mL, required to lower GH to 2.5 ng/mL or less. The serum concentration that elicited half of the Emax (EC50) was estimated as 0.206 ng/mL, showing a high sensitivity to lanreotide, with a predictably high interpatient variability of 200.75% reflecting the range of dosing regimens needed to control GH.