RESUMO
Antibody-drug conjugates (ADCs) contain a disease-receptor antibody and a payload drug connected via a linker. The payload delivery depends on both tumor properties and ADC characteristics. In this study, we used different linkers, attachment sites, and doses to modulate payload delivery of several ADCs bearing maytansinoids (e.g., DM1), auristatins (e.g., MMAE), and DNA alkylating agents [e.g., pyrrolo[2,1-c][1,4]benzodiazepine-dimer (PBD)] as payloads in HER2- or CD22-expressing xenograft models. The tumor growth inhibition and ADC stability and exposure data were collected and analyzed from these dosed animals. The trend analysis suggests that intratumoral payload exposures that directly related the combination of conjugate linker and dose correlate with the corresponding efficacies of three payload types in two antigen-expressing xenograft models. These preliminary correlations also suggest that a minimal threshold concentration of intratumoral payload is required to support sustained efficacy. In addition, an ADC can deliver an excessive level of payload to tumors that does not enhance efficacy ("Plateau" effect). In contrast to tumor payload concentrations, the assessments of systemic exposures of total antibody (Tab) as well as the linker, dose, site of attachment, plasma stability, and drug-to-antibody ratio changes of these ADCs did not consistently rationalize the observed ADC efficacies. The requirement of a threshold payload concentration for efficacy is further supported by dose fractionation studies with DM1-, MMAE-, and PBD-containing ADCs, which demonstrated that single-dose regimens showed better efficacies than fractionated dosing. Overall, this study demonstrates that 1) the linker and dose together determine the tissue payload concentration that correlates with the antitumor efficacy of ADCs and 2) an ADC can deliver an unnecessary level of payload to tumors in xenograft models.
Assuntos
Antineoplásicos Imunológicos/farmacocinética , Imunoconjugados/farmacocinética , Receptor ErbB-2/antagonistas & inibidores , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/antagonistas & inibidores , Ado-Trastuzumab Emtansina/administração & dosagem , Ado-Trastuzumab Emtansina/farmacocinética , Animais , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/química , Benzodiazepinas/química , Brentuximab Vedotin/administração & dosagem , Brentuximab Vedotin/farmacocinética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoconjugados/administração & dosagem , Camundongos , Camundongos Transgênicos , Pirróis/química , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Prior pharmacokinetic (PK) analyses of the antibody-drug conjugate (ADC) brentuximab vedotin (1.8 mg/kg every 3 weeks) in pediatric patients with relapsed/refractory hematologic malignancies found that patients aged <12 years exhibited decreased ADC area under the curve (AUC) compared with those aged ≥12 years. This population PK (POPPK) analysis used data from pediatric (NCT01492088) and adult (NCT00430846) studies of brentuximab vedotin to quantify body size effects on ADC exposure. Data were collected from 84 patients with a median age of 25.7 years (range, 7.7-87.3 years), 34 of whom (40.5%) were aged <18 years; median patient weight was 67 kg (range, 21-154 kg), and median body surface area was 1.8 m2 (range, 0.87-2.81 m2 ). ADC PK was described by a linear 3-compartment model with zero-order input and first-order elimination. POPPK modeling indicated that dosing brentuximab vedotin at 1.8 mg/kg every 3 weeks or 1.2 mg/kg every 2 weeks resulted in lower ADC AUC values in small/moderate-sized pediatric patients (<28 kg and 28-49 kg, respectively) compared with large pediatric/adult patients (50-100 kg). Dosing at 71.5 mg/m2 every 3 weeks and 47.7 mg/m2 every 2 weeks was predicted to achieve comparable AUC values across all body weight ranges and a similar AUC to that in the 50- to 100-kg group at the standard doses of 1.8 mg/kg every 3 weeks and 1.2 mg/kg every 2 weeks, respectively. These results have generated a hypothesis to support evaluation of brentuximab vedotin at 48 mg/m2 every 2 weeks in combination with adriamycin, vinblastine, and dacarbazine chemotherapy in an ongoing pediatric trial in frontline Hodgkin lymphoma (NCT02979522).
Assuntos
Antineoplásicos Imunológicos/farmacocinética , Brentuximab Vedotin/farmacocinética , Cálculos da Dosagem de Medicamento , Neoplasias Hematológicas/tratamento farmacológico , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Tamanho Corporal , Superfície Corporal , Peso Corporal , Criança , Ensaios Clínicos como Assunto , Simulação por Computador , Esquema de Medicação , Feminino , Humanos , Imunoconjugados/farmacocinética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Recidiva , Adulto JovemRESUMO
Model-informed drug development (MIDD) has become an important approach to improving clinical trial efficiency, optimizing drug dosing, and proposing drug labeling in the absence of dedicated clinical trials. For the first time, we developed a physiologically based pharmacokinetic (PBPK) model-based approach to assess CYP3A-mediated drug-drug interaction (DDI) risk for polatuzumab vedotin (Polivy), an anti-CD79b-vc-monomethyl auristatin E (MMAE) antibody-drug conjugate (ADC). The model was developed and verified using data from the existing clinical DDI study for brentuximab vedotin, a similar vc-MMAE ADC. Analogous to the brentuximab vedotin clinical study, polatuzumab vedotin at the proposed labeled dose was predicted to have a limited drug interaction potential with strong CYP3A inhibitor and inducer. Polatuzumab vedotin was also predicted to neither inhibit nor induce CYP3A. The present work demonstrated a high-impact application using a PBPK MIDD approach to predict the CYP3A-mediated DDI to enable drug labeling in the absence of any dedicated clinical DDI study. The key considerations for the PBPK report included in the Biologics License Application/Marketing Authorization Application submission, as well as the strategy and responses to address some of the critical and challenging questions from the health authorities following the submission are also discussed. Our experience and associated perspective using a PBPK approach to ultimately enable a drug interaction label claim for polatuzumab vedotin in lieu of a dedicated clinical DDI study, as well as the interactions with the regulatory agencies, further provides confidence in applying MIDD to accelerate the registration and approval of new drug therapies.
Assuntos
Anticorpos Monoclonais/farmacocinética , Desenvolvimento de Medicamentos , Interações Medicamentosas , Rotulagem de Medicamentos , Imunoconjugados/farmacocinética , Modelos Biológicos , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/química , Brentuximab Vedotin/farmacocinética , Simulação por Computador , Citocromo P-450 CYP3A/metabolismo , Humanos , Imunoconjugados/sangue , Imunoconjugados/química , Cetoconazol/farmacologia , Midazolam/farmacocinética , Oligopeptídeos/sangue , Oligopeptídeos/farmacocinética , Rifampina/farmacologiaRESUMO
Data on the treatment of pediatric patients with brentuximab vedotin are limited. The aims of the present study were to assess the safety and tolerability of brentuximab vedotin in Japanese children with relapsed or refractory Hodgkin's lymphoma (HL) or systemic anaplastic large-cell lymphoma (sALCL). Pediatric patients, aged 2-17 years, with relapsed or refractory HL or sALCL were recruited. Brentuximab vedotin were administered at 1.8 mg/kg via intravenous infusion once every 3 weeks. Primary endpoints were dose-limiting toxicity and safety. Between September 2016, and March 2018, six patients (median age 11.5, range 5-14 years), four with relapsed or refractory HL and two with relapsed or refractory sALCL were enrolled. Dose limiting toxicity was not observed in any of the six patients. Although three of six patients (50%) experienced at least one grade ≥ 3 adverse event, no patient experienced a serious adverse event. The pharmacokinetic profile of brentuximab vedotin in pediatric patients was comparable to that reported in adults. The proportion of patients who achieved overall response was 60% (95% confidence interval 14.7-94.7). Brentuximab vedotin at 1.8 mg/kg once every 3 weeks was considered tolerable in children with relapsed or refractory HL or sALCL.
Assuntos
Brentuximab Vedotin/administração & dosagem , Doença de Hodgkin/tratamento farmacológico , Antígeno Ki-1 , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Adolescente , Povo Asiático , Brentuximab Vedotin/efeitos adversos , Brentuximab Vedotin/farmacocinética , Criança , Pré-Escolar , Feminino , Humanos , Infusões Intravenosas , Masculino , Resultado do TratamentoRESUMO
The efficacy of the CD30-directed antibody-drug conjugate (ADC) brentuximab vedotin was established in combination with chemotherapy as frontline treatment for advanced classical Hodgkin's lymphoma in the randomized phase III ECHELON-1 study. Population pharmacokinetic (PK) and exposure-response models were developed to quantify sources of PK variability and relationships between exposure and safety/efficacy end points in ECHELON-1. The influence of patient-specific factors on the PK of the ADC and the microtubule-disrupting payload monomethyl auristatin E (MMAE) was investigated; none of the significant covariates had a clinically relevant impact. Exposure-response analyses evaluated relationships between time-averaged area under the curve (AUC; ADC, MMAE) and efficacy end points (ADC) or safety parameters (ADC, MMAE). Exposure-efficacy analyses supported consistent treatment benefit with brentuximab vedotin across observed exposure ranges. Exposure-safety analyses supported the recommended brentuximab vedotin starting dose (1.2 mg/kg every 2 weeks), and effective management of peripheral neuropathy and neutropenia with dose modification/reduction and febrile neutropenia with granulocyte colony-stimulating factor primary prophylaxis.