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1.
Eur J Clin Pharmacol ; 80(4): 529-543, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38252170

RESUMO

PURPOSE: A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for aztreonam-avibactam, an investigational combination antibiotic for serious Gram-negative bacterial infections. METHODS: Two iterations of PK models built from avibactam data in infected patients and aztreonam data in healthy subjects with "patient-like" assumptions were used in joint PTA analyses (primary target: aztreonam 60% fT > 8 mg/L, avibactam 50% fT > 2.5 mg/L) exploring patient variability, infusion durations, and adjustments for moderate (estimated creatinine clearance [CrCL] > 30 to ≤ 50 mL/min) and severe renal impairment (> 15 to ≤ 30 mL/min). Achievement of > 90% joint PTA and the impact of differential renal clearance were considerations in dose selection. RESULTS: Iteration 1 simulations for Phase I/IIa dose selection/modification demonstrated that 3-h and continuous infusions provide comparable PTA; avibactam dose drives joint PTA within clinically relevant exposure targets; and loading doses support more rapid joint target attainment. An aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h were selected for further evaluation. Iteration 2 simulations using expanded PK models supported an alteration to the regimen (500/167 mg loading; 1500/500 mg q6h maintenance 3-h infusions for CrCL > 50 mL/min) and selection of doses for renal impairment for Phase IIa/III clinical studies. CONCLUSION: A loading dose plus 3-h maintenance infusions of aztreonam-avibactam in a 3:1 fixed ratio q6h optimizes joint PTA. These analyses supported dose selection for the aztreonam-avibactam Phase III clinical program. CLINICAL TRIAL REGISTRATION: NCT01689207; NCT02655419; NCT03329092; NCT03580044.


Assuntos
Antibacterianos , Aztreonam , Humanos , Antibacterianos/farmacocinética , Compostos Azabicíclicos , Aztreonam/farmacocinética , Combinação de Medicamentos , Testes de Sensibilidade Microbiana
2.
HIV Clin Trials ; 14(3): 99-109, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23835512

RESUMO

PURPOSE: This open-label, nonrandomized, parallel-group study was conducted to explore the pharmacokinetics, safety, and tolerability of maraviroc in renally impaired subjects. METHODS: Subjects with normal renal function; mild, moderate, or severe renal impairment; or end-stage renal disease (ESRD) (n = 6 per group) were enrolled. Subjects with normal function (period 1), severe impairment, and ESRD received a single 300 mg dose of maraviroc. Subjects with normal function (period 2), mild impairment, and moderate impairment received 150 mg for 7 days at adjusted intervals of twice daily, once daily, and every 48 hours, respectively, with saquinavir/ritonavir (SQV/r). Maraviroc was quantified in plasma, urine, and dialysate by tandem high-performance liquid chromatography-mass spectrometry. RESULTS: With SQV/r, geometric mean steady-state maraviroc area under the plasma concentration-time curve for the dosing interval (AUCtau) was 5,341 (coefficient of variation [CV], 27%), 8,119 (35%), and 6,193 (27%) h•ng/mL, in normal function, mild, and moderate impairment groups, respectively. Without SQV/r, 2% to 3% of the maraviroc dose was recovered in urine versus 15% to 25% of steady-state dose when given with SQV/r. Moderate to high intersubject variability in exposure was noted. AUC from zero to infinity (AUCinf) was similar to historical single-dose data in subjects with ESRD: low in those with normal function, and high in those with severe impairment. Dialysis did not influence maraviroc exposure. Maraviroc was well tolerated. CONCLUSIONS: The data suggest that no dosing interval adjustments are required in subjects with renal impairment when maraviroc is administered alone. However, maraviroc dosing interval adjustment is warranted in renally impaired patients receiving potent CYP3A4 inhibitors. Reference to local prescribing information is recommended, because dose recommendations in renally impaired patients may differ between regions.


Assuntos
Fármacos Anti-HIV/farmacocinética , Cicloexanos/farmacocinética , Insuficiência Renal/metabolismo , Triazóis/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Adulto , Idoso , Fármacos Anti-HIV/efeitos adversos , Fármacos Anti-HIV/sangue , Área Sob a Curva , Estudos de Casos e Controles , Cicloexanos/efeitos adversos , Cicloexanos/sangue , Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Inibidores do Citocromo P-450 CYP3A , Feminino , Regulação da Expressão Gênica , Meia-Vida , Humanos , Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Masculino , Maraviroc , Pessoa de Meia-Idade , Diálise Renal , Índice de Gravidade de Doença , Triazóis/efeitos adversos , Triazóis/sangue
3.
Clin Pharmacol Ther ; 113(1): 182-195, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36239478

RESUMO

Ceftazidime-avibactam is a novel ß-lactam/ß-lactamase inhibitor combination developed to treat serious Gram-negative bacterial infections; approved indications include complicated urinary tract infection, complicated intra-abdominal infection, and hospital-acquired pneumonia including ventilator-associated pneumonia in patients ≥ 3 months old. Because of the predominantly renal clearance of ceftazidime and avibactam, dose adjustments (reductions) are required for patients with estimated creatinine clearance (CrCL) ≤ 50 mL/min. We describe the application of combined adult and pediatric population pharmacokinetic models in developing ceftazidime-avibactam dose recommendations for pediatric patients ≥ 2 to < 18 years old with body surface area-normalized CrCL ≤ 50 mL/min/1.73 m2 , including moderate, severe, or very severe renal impairment, or end-stage renal disease requiring hemodialysis, and for patients ≥ 3 months to < 2 years old with mild, moderate, or severe renal impairment. Models included allometric scaling for all subjects and simulations (1,000 subjects per age group, renal function group, and indication) were performed nonparametrically using post hoc random effects. Doses were selected based on simulated pediatric patients achieving steady-state exposures similar to adults and high probability of target attainment (using a simultaneous joint target for both ceftazidime and avibactam). Because there were few children with renal impairment in the ceftazidime-avibactam clinical trials, selected pediatric doses were guided by extrapolation and matching of adult exposures associated with efficacy and within established safety margins. The recommended doses for pediatric patients with estimated CrCL ≤ 50 mL/min/1.73 m2 use equivalent adjustments in dose quantity and/or administration interval (vs. the corresponding age group with normal renal function) as those for adults.


Assuntos
Ceftazidima , Insuficiência Renal , Adulto , Humanos , Criança , Lactente , Adolescente , Ceftazidima/farmacocinética , Antibacterianos/efeitos adversos , Combinação de Medicamentos , Inibidores de beta-Lactamases/uso terapêutico , Monobactamas , Rim/fisiologia
4.
Pediatr Infect Dis J ; 41(11): 885-890, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-35980827

RESUMO

BACKGROUND: Treatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of maraviroc in neonates to inform dosing regimens and expand available options. METHODS: Using maraviroc concentrations from neonates who received either a single dose or multiple doses of 8 mg/kg of maraviroc in the first 6 weeks of life, a population pharmacokinetic model was developed to determine the effects of age, sex, maternal efavirenz exposure and concomitant ARV therapy on maraviroc disposition. The final model was used in Monte Carlo simulations to generate expected exposures with recommended dosing regimens. RESULTS: A total of 396 maraviroc concentrations, collected in the first 4 days of life, at 1 week, at 4 weeks and at 6 weeks, from 44 neonates were included in the analysis. After allometrically scaling for weight, age less than 4 days was associated with a 44% decreased apparent clearance compared with participants 7 days to 6 weeks of life. There were no differences identified in apparent clearance or volume of distribution from ages 7 days to 6 weeks, sex, maternal efavirenz exposure or concomitant nevirapine therapy. Monte Carlo simulations with FDA-approved weight band dosing resulted in the majority of simulated patients (84.3%) achieving an average concentration of ≥75 ng/mL. CONCLUSIONS: While maraviroc apparent clearance is decreased in the first few days of life, the current FDA-approved maraviroc weight band dosing provides maraviroc exposures for neonates in the first 6 weeks of life, which were consistent with adult maraviroc exposure range. Maraviroc provides another antiretroviral treatment option for very young infants.


Assuntos
Infecções por HIV , Nevirapina , Adulto , Alcinos , Benzoxazinas/uso terapêutico , Ciclopropanos/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Maraviroc/uso terapêutico
5.
Clin Pharmacol Ther ; 111(3): 635-645, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34687548

RESUMO

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel ß-lactam ß-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2 .


Assuntos
Antibacterianos/farmacocinética , Compostos Azabicíclicos/farmacocinética , Ceftazidima/farmacocinética , Inibidores de beta-Lactamases/farmacocinética , Adolescente , Antibacterianos/uso terapêutico , Compostos Azabicíclicos/uso terapêutico , Ceftazidima/uso terapêutico , Criança , Pré-Escolar , Combinação de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Feminino , Bactérias Gram-Negativas/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos , Lactente , Infecções Intra-Abdominais/tratamento farmacológico , Infecções Intra-Abdominais/microbiologia , Masculino , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Pneumonia Associada à Ventilação Mecânica/microbiologia , Probabilidade , Infecções Urinárias/tratamento farmacológico , Infecções Urinárias/microbiologia , Inibidores de beta-Lactamases/uso terapêutico
6.
J Pharmacokinet Pharmacodyn ; 38(1): 41-61, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21088872

RESUMO

Using simulated viral load data for a given maraviroc monotherapy study design, the feasibility of different algorithms to perform parameter estimation for a pharmacokinetic-pharmacodynamic-viral dynamics (PKPD-VD) model was assessed. The assessed algorithms are the first-order conditional estimation method with interaction (FOCEI) implemented in NONMEM VI and the SAEM algorithm implemented in MONOLIX version 2.4. Simulated data were also used to test if an effect compartment and/or a lag time could be distinguished to describe an observed delay in onset of viral inhibition using SAEM. The preferred model was then used to describe the observed maraviroc monotherapy plasma concentration and viral load data using SAEM. In this last step, three modelling approaches were compared; (i) sequential PKPD-VD with fixed individual Empirical Bayesian Estimates (EBE) for PK, (ii) sequential PKPD-VD with fixed population PK parameters and including concentrations, and (iii) simultaneous PKPD-VD. Using FOCEI, many convergence problems (56%) were experienced with fitting the sequential PKPD-VD model to the simulated data. For the sequential modelling approach, SAEM (with default settings) took less time to generate population and individual estimates including diagnostics than with FOCEI without diagnostics. For the given maraviroc monotherapy sampling design, it was difficult to separate the viral dynamics system delay from a pharmacokinetic distributional delay or delay due to receptor binding and subsequent cellular signalling. The preferred model included a viral load lag time without inter-individual variability. Parameter estimates from the SAEM analysis of observed data were comparable among the three modelling approaches. For the sequential methods, computation time is approximately 25% less when fixing individual EBE of PK parameters with omission of the concentration data compared with fixed population PK parameters and retention of concentration data in the PD-VD estimation step. Computation times were similar for the sequential method with fixed population PK parameters and the simultaneous PKPD-VD modelling approach. The current analysis demonstrated that the SAEM algorithm in MONOLIX is useful for fitting complex mechanistic models requiring multiple differential equations. The SAEM algorithm allowed simultaneous estimation of PKPD and viral dynamics parameters, as well as investigation of different model sub-components during the model building process. This was not possible with the FOCEI method (NONMEM version VI or below). SAEM provides a more feasible alternative to FOCEI when facing lengthy computation times and convergence problems with complex models.


Assuntos
Algoritmos , Cicloexanos/farmacocinética , Inibidores da Fusão de HIV/farmacocinética , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV/efeitos dos fármacos , Modelos Estatísticos , Triazóis/farmacocinética , Simulação por Computador , Cicloexanos/farmacologia , Cicloexanos/uso terapêutico , HIV/fisiologia , Inibidores da Fusão de HIV/farmacologia , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Humanos , Maraviroc , Projetos de Pesquisa , Software , Triazóis/farmacologia , Triazóis/uso terapêutico , Carga Viral
7.
Clin Pharmacol Ther ; 110(1): 132-140, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33280106

RESUMO

Pregabalin is approved in multiple countries as adjunctive therapy for adult patients with focal onset seizures (FOS; previously termed partial onset seizures). This study used population pharmacokinetic (PK) and exposure-response (E-R) analyses from pooled pregabalin concentration and efficacy data to compare pregabalin exposure and E-R relationships in pediatric and adult patients with FOS, to support pediatric dosage recommendations. A one-compartment disposition model was used, with first-order absorption and body surface area-normalized creatinine clearance on clearance. Individual pregabalin average steady-state concentrations were predicted and used in an E-R analysis of efficacy. The E-R relationship of pregabalin was similar in pediatric (4-16 years) and adult patients with FOS after accounting for differences in baseline natural log-transformed 28-day seizure rate and placebo effect. Population PK simulations showed that children aged 4-16 years and weighing ≥ 30 kg required pregabalin 2.5-10 mg/kg/day to achieve similar pregabalin exposure at steady-state to adult patients receiving the approved doses of 150-600 mg/day. For children 4-16 years weighing < 30 kg, a higher pregabalin dose of 3.5-14 mg/kg/day was required to achieve equivalent exposure at steady-state. The results support the dosage guidance provided in the pregabalin prescribing label, whereby pediatric patients (4-16 years) weighing < 30 kg should receive a 40% higher pregabalin dose (per kg of body weight) than patients weighing ≥ 30 kg to achieve similar exposure. Our combined modeling approach may provide guidance for future extrapolation assessment from adult to pediatric patients.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsias Parciais/tratamento farmacológico , Modelos Biológicos , Pregabalina/administração & dosagem , Adolescente , Adulto , Fatores Etários , Idoso , Anticonvulsivantes/farmacocinética , Criança , Pré-Escolar , Creatinina/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Pregabalina/farmacocinética , Resultado do Tratamento , Adulto Jovem
8.
CPT Pharmacometrics Syst Pharmacol ; 10(6): 551-563, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33687148

RESUMO

A model-informed drug development approach was used to select ceftaroline fosamil high-dose regimens for pediatric patients with complicated skin and soft-tissue infections caused by Staphylococcus aureus with a ceftaroline minimum inhibitory concentration (MIC) of 2 or 4 mg/L. Steady-state ceftaroline concentrations were simulated using a population pharmacokinetics (PK) model for ceftaroline fosamil and ceftaroline including data from 304 pediatric subjects and 944 adults. Probability of target attainment (PTA) for various simulated pediatric high-dose regimens and renal function categories were calculated based on patients achieving 35% fT>MIC (S. aureus PK/pharmacodynamic target for 2-log10 bacterial killing). For extrapolation of efficacy, simulated exposures and PTA were compared to adults with normal renal function receiving high-dose ceftaroline fosamil (600 mg 2-h infusions every 8 h). For safety, predicted ceftaroline exposures were compared with observed pediatric and adult data. Predicted ceftaroline exposures for the approved pediatric high-dose regimens (12, 10, or 8 mg/kg by 2-h infusions every 8 h for patients aged >2 to <18 years with normal/mild, moderate, or severe renal impairment, respectively; 10 mg/kg by 2-h infusions every 8 h for patients aged ≥2 months to <2 years with normal renal function/mild impairment) were well matched to adults with normal renal function. Median predicted maximum concentration at steady state (Cmax,ss ) and area under the plasma concentration-time curve over 24 h at steady state pediatric to adult ratios were 0.907-1.33 and 0.940-1.41, respectively. PTAs (>99% and ≥81% for MICs of 2 and 4 mg/L, respectively) matched or exceeded the adult predictions. Simulated Cmax,ss values were below the maximum observed data in other indications, including a high-dose pediatric pneumonia trial, which reported no adverse events related to high exposure.


Assuntos
Antibacterianos/administração & dosagem , Cefalosporinas/administração & dosagem , Modelos Biológicos , Dermatopatias Infecciosas/tratamento farmacológico , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus , Adolescente , Adulto , Antibacterianos/sangue , Antibacterianos/farmacocinética , Cefalosporinas/sangue , Cefalosporinas/farmacocinética , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Simulação por Computador , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Testes de Sensibilidade Microbiana , Insuficiência Renal/sangue , Insuficiência Renal/metabolismo , Dermatopatias Infecciosas/sangue , Dermatopatias Infecciosas/metabolismo , Infecções dos Tecidos Moles/sangue , Infecções dos Tecidos Moles/metabolismo , Infecções Estafilocócicas/sangue , Infecções Estafilocócicas/metabolismo , Ceftarolina
9.
AIDS ; 35(3): 419-427, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33252481

RESUMO

OBJECTIVE: The aim of this study was to evaluate safety and pharmacokinetics of maraviroc administered with standard antiretroviral prophylaxis to HIV-1 exposed infants and to determine the appropriate dose of maraviroc during the first 6 weeks of life. DESIGN: A phase I, multicentre, open-label study enrolling two sequential cohorts. METHODS: IMPAACT 2007 participants enrolled by day 3 of life and were stratified by exposure to maternal efavirenz. Cohort 1 participants received two single 8 mg/kg maraviroc doses 1 week apart with pharmacokinetic sampling after each dose. Cohort 2 participants received 8 mg/kg maraviroc twice daily through 6 weeks of life with pharmacokinetic sampling at weeks 1 and 4. Maraviroc exposure target was Cavg at least 75 ng/ml. Laboratory and clinical evaluations assessed safety. RESULTS: Fifteen Cohort 1 and 32 Cohort 2 HIV-exposed neonates were enrolled (median gestational age 39 weeks, 51% male). All 13 evaluable Cohort 1 infants met the pharmacokinetic target. Median exposure for the 25 evaluable Cohort 2 infants met the pharmacokinetic target but variability was high, with 17-33% of infants below target at Weeks 1 and 4. Pharmacokinetic target achievement was similar between efavirenz exposure strata. No Grade 3+ toxicities, early study or treatment discontinuations due to maraviroc occurred. CONCLUSION: Median maraviroc exposure met the Cavg target in neonates receiving 8 mg/kg twice daily, although exposures were variable. Maternal efavirenz use did not impact maraviroc exposure and no discontinuations were due to maraviroc toxicity/intolerance. No infants acquired HIV-1 infection during follow-up. Maraviroc 8 mg/kg twice daily appears well tolerated during the first 6 weeks of life.


Assuntos
Infecções por HIV , HIV-1 , Adulto , Antirretrovirais/uso terapêutico , Estudos de Coortes , Cicloexanos/efeitos adversos , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Recém-Nascido , Masculino , Maraviroc
11.
Br J Clin Pharmacol ; 69(4): 336-45, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20406218

RESUMO

AIM: To assess the translation of pharmacokinetic-pharmacodynamic (PK-PD) relationships for heart rate effects of PF-00821385 in dog and man. METHODS: Cardiovascular telemetric parameters and concentration data were available for animals receiving active doses (0.5-120 mg kg(-1), n= 4) or vehicle. PF-00821385 was administered to 24 volunteers and pharmacokinetic and vital signs data were collected. PK-PD models were fitted using nonlinear mixed effects. RESULTS: Compartmental models with linear absorption and clearance were used to describe pharmacokinetic disposition in animal and man. Diurnal variation in heart and pulse rate was best described with a single cosine function in both dog and man. Canine and human heart rate change were described by a linear model with free drug slope 1.76 bpm microM(-1)[95% confidence interval (CI) 1.17, 2.35] in the dog and 0.76 bpm microM(-1) (95% CI 0.54, 1.14) in man. CONCLUSIONS: The preclinical translational of concentration-response has been described and the potential for further interspecies extrapolation and optimization of clinical trial design is addressed.


Assuntos
Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/farmacocinética , Frequência Cardíaca/efeitos dos fármacos , Piperazinas/farmacologia , Piridinas/farmacologia , Administração Oral , Adulto , Animais , Fármacos Anti-HIV/administração & dosagem , Estudos de Coortes , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Infecções por HIV/tratamento farmacológico , Humanos , Modelos Lineares , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Adulto Jovem
12.
J Pharmacokinet Pharmacodyn ; 37(2): 157-77, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20204473

RESUMO

Disease progression modelling can provide information about the time course and outcome of pharmacological intervention on the disease. The basic PK/PD principles of proliferative and circular systems within the context of modelling disease progression and the effect of treatment thereupon are illustrated with the goal to better understand/predict eventual clinical outcome. Circular/proliferative systems can be very complex. To facilitate the understanding of how a dosing regimen can be defined in such systems we have shown the derivation of a system parameter named the Reproduction Minimum Inhibitory Concentration (RMIC) which represents the critical concentration at which the system switches from growth to extinction. The RMIC depends on two parameters (RMIC = (R(0) - 1) x IC(50)): the basic reproductive ratio (R(0)) a fundamental parameter of the circular/proliferative system that represents the number of offspring produced by one replicating species during its lifespan, and the IC(50), the potency of the drug to inhibit the proliferation of the system. The RMIC is constant for a given system and a given drug and represents the lowest concentration that needs to be achieved for eradication of the system. When exposure is higher than the RMIC, success can be expected in the long term. Time varying inhibition of replicating species proliferation is a natural consequence of the time varying inhibitor drug concentrations and when combined with the dynamics of the circular/proliferative system makes it difficult to predict the eventual outcome. Time varying inhibition of proliferative/circular systems can be handled by calculating the equivalent effective constant concentration (ECC), the constant plasma concentration that would give rise to the average inhibition at steady state. When ECC is higher than the RMIC, eradication of the system can be expected. In addition, it is shown that scenarios that have the same steady state ECC whatever the dose, dosage schedule or PK parameters have also the same average R (0) in the presence of the inhibitor (i.e. R (0-INH)) and therefore lead to the same outcome. This allows predicting equivalent active doses and dosing schedules in circular and proliferative systems when the IC(50) and pharmacokinetic characteristics of the drugs are known. The results from the simulations performed demonstrate that, for a given system (defined by its RMIC), treatment success depends mainly on the pharmacokinetic characteristics of the drug and the dosing schedule.


Assuntos
Progressão da Doença , Modelos Biológicos , Farmacocinética , Farmacologia/métodos , Antivirais/farmacocinética , Antivirais/farmacologia , Humanos , Modelos Logísticos , Testes de Sensibilidade Microbiana , Carga Viral/efeitos dos fármacos , Viroses/tratamento farmacológico , Viroses/metabolismo
13.
Clin Pharmacol Ther ; 108(2): 316-325, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32189334

RESUMO

In a pooled population analysis, we investigated the pharmacokinetics of i.v. anidulafungin in four studies across a full range of adult and pediatric ages in patients with confirmed, suspected, or at high risk of invasive candidiasis (IC). Relationships between anidulafungin exposure and key efficacy end points (global response of success and all-cause mortality) and safety end points (all-cause hepatic or gastrointestinal adverse events) in all patients and separately in pediatric patients and the appropriate dosing regimen for IC treatment in pediatric patients were evaluated. Pediatric patients received a 3.0 mg/kg (maximum 200 mg) i.v. loading dose and 1.5 mg/kg (maximum 100 mg) daily thereafter. Adults received a 200 mg i.v. loading dose and 100 mg daily thereafter. Estimated systemic anidulafungin exposures were similar across age groups (neonates to adults) at the weight-based doses studied in pediatric patients. No clear associations were identified between anidulafungin exposure and efficacy or safety end points.


Assuntos
Anidulafungina/farmacocinética , Antifúngicos/farmacocinética , Candidíase Invasiva/tratamento farmacológico , Modelos Biológicos , Administração Intravenosa , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Anidulafungina/administração & dosagem , Anidulafungina/efeitos adversos , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Candidíase Invasiva/diagnóstico , Candidíase Invasiva/microbiologia , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Monitoramento de Medicamentos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
14.
Br J Clin Pharmacol ; 68(3): 355-69, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19740392

RESUMO

AIMS: To model the basic pharmacokinetic (PK) characteristics of maraviroc to construct an integrated semi-mechanistic PK model for use in later population PK analyses. METHODS: Three analyses were performed utilizing intravenous, oral and radiolabel data. Firstly, a PK disposition model was developed from data from 20 healthy males who received 3, 10 or 30 mg of intravenous maraviroc. Secondly, a sigmoid E(max)vs dose model of dose-normalized non-compartmental AUC from oral dosing in 134 healthy young males and females across five phase 1 studies was constructed. This described absorption dose non-linearities and tested for the influence of food, formulation and dose frequency on model parameters. The third analysis developed a mass balance model for both absorption and disposition of maraviroc with 300 mg solution and predicted the mass balance after administration of 100 mg tablet formulation. RESULTS: A four-compartment PK model best described the intravenous data and no influence of dose was found on clearance. Total clearance was 48 l h(-1) (2.2% SE). The main covariate effect in the non-compartmental analysis reproduced the dose-dependency of food through a five-fold increase in the ED(50) of the sigmoid E(max) model. The mass balance models calculated that 33.3% and 22.9% of 300 mg solution and 100 mg tablet doses, respectively, are systemically available, and first-pass metabolism extracts 62% of an absorbed dose, estimating a hepatic blood flow of 101 l h(-1). CONCLUSIONS: The analysis demonstrates a novel integration approach to build a maraviroc semi-mechanistic population PK model for further use in volunteers and patients.


Assuntos
Fármacos Anti-HIV/farmacocinética , Cicloexanos/farmacocinética , Modelos Biológicos , Triazóis/farmacocinética , Administração Oral , Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/uso terapêutico , Ensaios Clínicos Fase I como Assunto , Cicloexanos/administração & dosagem , Cicloexanos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Injeções Intravenosas , Masculino , Maraviroc , Taxa de Depuração Metabólica , Modelos Estatísticos , Triazóis/administração & dosagem , Triazóis/uso terapêutico
15.
Infect Dis Ther ; 8(2): 185-198, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30963520

RESUMO

INTRODUCTION: This retrospective analysis compares the probability of target attainment (PTA) for ceftriaxone, levofloxacin and ceftaroline fosamil against Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae in a representative patient population with moderate-to-severe community-acquired pneumonia (CAP). METHODS: Published pharmacokinetic (PK) models for levofloxacin and ceftriaxone, and an existing model for ceftaroline, were used with standard dosage regimens for simulating individual PK data with covariates representative of patients with CAP (5000 patients/drug regimen). PTA for clinically relevant pharmacokinetic/pharmacodynamic (PK/PD) targets was calculated from steady state PK profiles for a range of minimum inhibitory concentrations (MICs). Cumulative fractions of response (CFRs) were also calculated using MIC distributions from 2012 to 2017 global surveillance data. RESULTS: Ceftaroline fosamil (600 mg q12 h) achieved > 90% PTA at all exposure targets for each pathogen at European Committee on Antimicrobial Susceptibility Testing (EUCAST)/Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints, and CFRs were > 99%. Ceftriaxone, but not levofloxacin, achieved 100% PTA and > 90% CFR against S. pneumoniae. Both levofloxacin and ceftriaxone achieved high PTA and CFR against H. influenzae. Levofloxacin achieved PTAs < 90% at EUCAST/CLSI breakpoints and ceftriaxone achieved PTAs < 90% at MICs up to 2 mg/L against S. aureus; both agents produced generally low CFRs against S. aureus (except levofloxacin against methicillin-sensitive S. aureus), reflecting the lack of activity of these agents against methicillin-resistant S. aureus. CONCLUSION: Ceftaroline fosamil demonstrated higher overall PTA rates than levofloxacin and ceftriaxone, in particular against S. aureus. These results provide insight regarding the potential comparative efficacy of the described antibiotics for moderate-to-severe CAP. FUNDING: Pfizer.

16.
J Clin Pharmacol ; 59(1): 139-152, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30192390

RESUMO

Maraviroc is a C-C chemokine receptor type-5 antagonist approved for the treatment of HIV-1. Previous studies show that cytochrome P450 3A5 (CYP3A5) plays a role in maraviroc metabolism. CYP3A5 is subject to a genetic polymorphism. The presence of 2 functional alleles (CYP3A5*1/*1) confers the extensive metabolism phenotype, which is rare in whites but common in blacks. The effect of CYP3A5 genotype on maraviroc and/or metabolite pharmacokinetics was evaluated in 2 clinical studies: a post hoc analysis from a phase 2b/3 study (NCT00098293) conducted in 494 HIV-1-infected subjects (study 1) in which the impact on maraviroc efficacy in 303 subjects was also assessed, and a study conducted in 47 healthy volunteers (study 2). In study 2 (NCT02625207), extensive metabolizers had 26% to 37% lower mean area under the concentration-time curve compared with poor metabolizers (no CYP3A5*1 alleles). This effect diminished to 17% in the presence of potent CYP3A inhibition. The effect of CYP3A5 genotype was greatest in the formation of the metabolite (1S,2S)-2-hydroxymaraviroc. In study 1, the CYP3A5*1/*1 genotype unexpectedly had higher maraviroc area under the curve predictions (20%) compared with those with no CYP3A5*1 alleles. The reason for this disparity remains unclear. The proportions of subjects with viral loads <50 and <400 copies/mL for maraviroc were comparable among all 3 CYP3A5 genotypes. In both studies maraviroc exposures were in the range of near-maximal viral inhibition in the majority of subjects. These results demonstrate that although CYP3A5 contributes to the metabolism of maraviroc, CYP3A5 genotype does not affect the clinical response to maraviroc in combination treatment of HIV-1 infection at approved doses.


Assuntos
Citocromo P-450 CYP3A/genética , Inibidores da Fusão de HIV/farmacocinética , Inibidores da Fusão de HIV/uso terapêutico , Infecções por HIV , HIV-1 , Maraviroc/farmacocinética , Maraviroc/uso terapêutico , Adulto , Método Duplo-Cego , Feminino , Genótipo , Inibidores da Fusão de HIV/sangue , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/metabolismo , Voluntários Saudáveis , Humanos , Masculino , Maraviroc/sangue , Pessoa de Meia-Idade , Polimorfismo Genético , Resultado do Tratamento , Adulto Jovem
17.
Br J Clin Pharmacol ; 65 Suppl 1: 95-106, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18333871

RESUMO

AIM: To develop a novel combined viral dynamics/operational model of (ant-)agonism that describes the pharmacodynamic effects of maraviroc, a noncompetitive CCR5 inhibitor, on viral load. METHODS: A common theoretical framework based on receptor theory and the operational model of (ant-)agonism has been developed to describe the binding of maraviroc to the CCR5 receptor and the subsequent decrease in viral load. The anchor point of the operational model in the differential equations of the viral dynamic model is the infection rate constant; this is assumed to be dependent on the number of free activated receptors on each target cell. RESULTS: The new model provides one explanation for the apparent discrepancy between the in vivo binding of maraviroc to the CCR5 receptor (K(D) = 0.089 ng ml(-1)) and the estimated in vivo inhibition (IC(50) = 8 ng ml(-1)) of the infection rate. The estimated K(E) value of the operational model indicates that only 1.2% of free activated receptors are utilized to elicit 50% of the maximum infection rate. CONCLUSIONS: The developed model suggests that the target cells, when activated, express more receptors (spare receptors) than needed. In the presence of maraviroc these spare receptors first require blocking before any decrease in the infection rate, and consequently in the viral load at equilibrium, can be detected. The model allows the simultaneous simulation of the binding of maraviroc to the CCR5 receptor and the change in viral load after both short- and long-term treatment.


Assuntos
Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Cicloexanos/farmacocinética , Infecções por HIV/tratamento farmacológico , Triazóis/farmacocinética , Simulação por Computador , Humanos , Maraviroc , Modelos Biológicos , Modelos Estatísticos , Carga Viral
18.
Br J Clin Pharmacol ; 65 Suppl 1: 76-85, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18333869

RESUMO

AIMS: To develop a population pharmacokinetic model for maraviroc, a noncompetitive CCR5 antagonist, after oral administration of tablets to healthy volunteers and asymptomatic HIV-infected subjects and to quantify the inherent variability and influence of covariates on the parameters of the model. METHODS: Rich pharmacokinetic data available from 15 studies in healthy volunteers (n = 365) and two studies in asymptomatic HIV-infected subjects (n = 48) were analysed using NONMEM. Maraviroc was administered as single or multiple oral tablet doses under fasted and fed conditions. Doses ranged from 100 to 1800 mg day(-1). RESULTS: A two-compartment model parameterized to separate out absorption and clearance components on bioavailability was used. Absorption was described by a lagged first-order process. A sigmoid E(max) model described the effect of dose on absorption. A visual predictive check and nonparametric bootstrap evaluation confirmed that the model was a good description of the data. Typical CL, V(c) and V(p) values for a 30-year-old non-Asian are 51.5 l h(-1), 132 l and 277 l, respectively. CONCLUSIONS: For the typical non-Asian subject, fasted bioavailability increased asymptotically with dose from 24% at 100 mg to 33% at 600 mg. A high-fat meal taken with maraviroc reduced exposure by 43% for a 100-mg dose to approximately 25% at doses of 600 mg. The typical Asian subject had a 26.5% higher AUC than the typical non-Asian subject irrespective of dose, a difference not considered to be clinically relevant. None of the other covariates tested had any clinically relevant effects on exposure.


Assuntos
Fármacos Anti-HIV/farmacocinética , Antagonistas dos Receptores CCR5 , Cicloexanos/farmacocinética , Infecções por HIV/tratamento farmacológico , Triazóis/farmacocinética , Adolescente , Adulto , Simulação por Computador , Feminino , Humanos , Masculino , Maraviroc , Pessoa de Meia-Idade , Modelos Biológicos , Modelos Estatísticos , Ensaios Clínicos Controlados Aleatórios como Assunto
19.
Clin Transl Sci ; 11(1): 54-62, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29106053

RESUMO

Dissociated agonists of the glucocorticoid receptor (DAGRs) show similar antiinflammatory effects but improved tolerability compared with standard glucocorticoid receptor (GR) agonists. The prodrug fosdagrocorat (PF-04171327), with active DAGR metabolite PF-00251802 (Metabolite-1), is postulated to show superior efficacy over placebo and prednisone in patients with moderate to severe rheumatoid arthritis (RA). We investigated the population pharmacokinetics of active Metabolite-1 and its active metabolite PF-04015475 (Metabolite-2) in patients with moderate to severe RA enrolled in a 12-week, phase II, randomized, double-blind study (NCT01393639). A simultaneous fit of a two-compartment model for Metabolite-1 and a one-compartment model for Metabolite-2 provided an adequate fit to the data. Significant covariates included weight, with an additional female effect on clearance of Metabolite-1 (∼26%) and Metabolite-2 (∼33%) compared with males. Age influenced clearance of Metabolite-1. In combination, age, weight, and sex predicted >twofold differences in area under the concentration-time curve of Metabolite-1 at the extremes.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Variação Biológica da População , Organofosfatos/farmacocinética , Fenantrenos/farmacocinética , Pró-Fármacos/farmacocinética , Receptores de Glucocorticoides/agonistas , Administração Oral , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Artrite Reumatoide/diagnóstico , Peso Corporal , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Glucocorticoides/farmacocinética , Glucocorticoides/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Organofosfatos/administração & dosagem , Organofosfatos/efeitos adversos , Fenantrenos/administração & dosagem , Fenantrenos/efeitos adversos , Prednisona/farmacocinética , Prednisona/uso terapêutico , Pró-Fármacos/administração & dosagem , Pró-Fármacos/efeitos adversos , Índice de Gravidade de Doença , Fatores Sexuais , Adulto Jovem
20.
AAPS J ; 20(3): 52, 2018 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-29549459

RESUMO

Every year, the pharmaceutical industry generates a large number of scientific reports related to drug research, development, and regulatory submissions. Many of these reports are created using text processing tools such as Microsoft Word. Given the large number of figures, tables, references, and other elements, this is often a tedious task involving hours of copying and pasting and substantial efforts in quality control (QC). In the present article, we present the LaTeX-based open-source reporting platform, PharmTeX, a community-based effort to make reporting simple, reproducible, and user-friendly. The PharmTeX creators put a substantial effort into simplifying the sometimes complex elements of LaTeX into user-friendly functions that rely on advanced LaTeX and Perl code running in the background. Using this setup makes LaTeX much more accessible for users with no prior LaTeX experience. A software collection was compiled for users not wanting to manually install the required software components. The PharmTeX templates allow for inclusion of tables directly from mathematical software output as well and figures from several formats. Code listings can be included directly from source. No previous experience and only a few hours of training are required to start writing reports using PharmTeX. PharmTeX significantly reduces the time required for creating a scientific report fully compliant with regulatory and industry expectations. QC is made much simpler, since there is a direct link between analysis output and report input. PharmTeX makes available to report authors the strengths of LaTeX document processing without the need for extensive training. Graphical Abstract ᅟ.


Assuntos
Indústria Farmacêutica/organização & administração , Relatório de Pesquisa , Design de Software , Fluxo de Trabalho , Automação , Controle de Qualidade , Interface Usuário-Computador
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