ABSTRACT
Immune checkpoint blockade has become standard treatment for many types of cancer. Such therapy is indicated most often in patients with advanced or metastatic disease but has been increasingly used as adjuvant therapy in those with early-stage disease. Adverse events include immune-related organ inflammation resembling autoimmune diseases. We describe a case of severe immune-related gastroenterocolitis in a 4-month-old infant who presented with intractable diarrhea and failure to thrive after in utero exposure to pembrolizumab. Known causes of the symptoms were ruled out, and the diagnosis of pembrolizumab-induced immune-related gastroenterocolitis was supported by the results of histopathological assays, immunophenotyping, and analysis of the level of antibodies against programmed cell death protein 1 (PD-1). The infant's condition was successfully treated with prednisolone and infliximab.
Subject(s)
Gastroenteritis , Immune Checkpoint Inhibitors , Neoplasms , Humans , Infant , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Enteritis/chemically induced , Enteritis/diagnosis , Enteritis/drug therapy , Enteritis/immunology , Neoplasms/drug therapy , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/therapeutic use , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Failure to Thrive/chemically induced , Failure to Thrive/immunology , Diarrhea, Infantile/chemically induced , Diarrhea, Infantile/immunology , Gastroenteritis/chemically induced , Gastroenteritis/diagnosis , Gastroenteritis/drug therapy , Gastroenteritis/immunology , Enterocolitis/chemically induced , Enterocolitis/diagnosis , Enterocolitis/drug therapy , Enterocolitis/immunology , Programmed Cell Death 1 Receptor/immunologyABSTRACT
Treatment regimens for post-kala-azar dermal leishmaniasis (PKDL) are usually extrapolated from those for visceral leishmaniasis (VL), but drug pharmacokinetics (PK) can differ due to disease-specific variations in absorption, distribution, and elimination. This study characterized PK differences in paromomycin and miltefosine between 109 PKDL and 264 VL patients from eastern Africa. VL patients showed 0.55-fold (95%CI: 0.41-0.74) lower capacity for paromomycin saturable reabsorption in renal tubules, and required a 1.44-fold (1.23-1.71) adjustment when relating renal clearance to creatinine-based eGFR. Miltefosine bioavailability in VL patients was lowered by 69% (62-76) at treatment start. Comparing PKDL to VL patients on the same regimen, paromomycin plasma exposures were 0.74-0.87-fold, while miltefosine exposure until the end of treatment day was 1.4-fold. These pronounced PK differences between PKDL and VL patients in eastern Africa highlight the challenges of directly extrapolating dosing regimens from one leishmaniasis presentation to another.
ABSTRACT
BACKGROUND: Therapeutic drug monitoring (TDM) - performing dose adjustments based on measured drug levels and established pharmacokinetic (PK) targets - could optimise treatment with drugs that show large interpatient variability in exposure. We evaluated the feasibility of TDM for multiple oral targeted therapies. Here we report on drugs for which routine TDM is not feasible. METHODS: We evaluated drug cohorts from the Dutch Pharmacology Oncology Group - TDM study. Based on PK levels taken at pre-specified time points, PK-guided interventions were performed. Feasibility of TDM was evaluated, and based on the success and practicability of TDM, cohorts could be closed. RESULTS: For 10 out of 24 cohorts TDM was not feasible and inclusion was closed. A high incidence of adverse events resulted in closing the cabozantinib, dabrafenib/trametinib, everolimus, regorafenib and vismodegib cohort. The enzalutamide and erlotinib cohorts were closed because almost all PK levels were above target. Other, non-pharmacological reasons led to closing the palbociclib, olaparib and tamoxifen cohort. CONCLUSIONS: Although TDM could help personalising treatment for many drugs, the above-mentioned reasons can influence its feasibility, usefulness and clinical applicability. Therefore, routine TDM is not advised for cabozantinib, dabrafenib/trametinib, enzalutamide, erlotinib, everolimus, regorafenib and vismodegib. Nonetheless, TDM remains valuable for individual clinical decisions.
Subject(s)
Drug Monitoring , Neoplasms , Pyridines , Humans , Drug Monitoring/methods , Prospective Studies , Neoplasms/drug therapy , Pyridines/pharmacokinetics , Pyridines/administration & dosage , Feasibility Studies , Administration, Oral , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Molecular Targeted Therapy , Imidazoles/pharmacokinetics , Imidazoles/administration & dosage , Anilides/pharmacokinetics , Anilides/administration & dosage , Male , Everolimus/pharmacokinetics , Everolimus/administration & dosage , Female , Oximes/pharmacokinetics , Oximes/administration & dosage , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacokinetics , Phenylthiohydantoin/administration & dosage , Nitriles/pharmacokinetics , Nitriles/administration & dosage , Phenylurea Compounds , Pyridones , Pyrimidinones , Piperazines , BenzamidesABSTRACT
INTRODUCTION: Post-kala-azar dermal leishmaniasis (PKDL) arises as a dermal complication following a visceral leishmaniasis (VL) infection. Current treatment options for PKDL are unsatisfactory, and there is a knowledge gap regarding the distribution of antileishmanial compounds within human skin. The present study investigated the skin distribution of miltefosine in PKDL patients, with the aim to improve the understanding of the pharmacokinetics at the skin target site in PKDL. METHODS: Fifty-two PKDL patients underwent treatment with liposomal amphotericin B (20â mg/kg) plus miltefosine (allometric dosing) for 21 days. Plasma concentrations of miltefosine were measured on study days 8, 15, 22 and 30, while a punch skin biopsy was taken on day 22. A physiologically based pharmacokinetic (PBPK) model was developed to evaluate the distribution of miltefosine into the skin. RESULTS: Following the allometric weight-based dosing regimen, median miltefosine concentrations on day 22 were 43.73â µg/g (IQR: 21.94-60.65â µg/g) in skin and 33.29â µg/mL (IQR: 25.9-42.58â µg/mL) in plasma. The median individual concentration ratio of skin to plasma was 1.19 (IQR: 0.79-1.9). In 87% (45/52) of patients, skin exposure was above the suggested EC90 PK target of 10.6â mg/L associated with in vitro susceptibility. Simulations indicated that the residence time of miltefosine in the skin would be more than 2-fold longer than in plasma, estimated by a mean residence time of 604 versus 266 hours, respectively. CONCLUSION: This study provides the first accurate measurements of miltefosine penetration into the skin, demonstrating substantial exposure and prolonged retention of miltefosine within the skin. These findings support the use of miltefosine in cutaneous manifestations of leishmaniasis. In combination with parasitological and clinical data, these results are critical for the future optimization of combination therapies with miltefosine in the treatment of PKDL.
Subject(s)
Amphotericin B , Antiprotozoal Agents , Leishmaniasis, Cutaneous , Leishmaniasis, Visceral , Phosphorylcholine , Skin , Humans , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/pharmacokinetics , Phosphorylcholine/administration & dosage , Phosphorylcholine/therapeutic use , Antiprotozoal Agents/pharmacokinetics , Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/therapeutic use , Male , Adult , Leishmaniasis, Cutaneous/drug therapy , Leishmaniasis, Cutaneous/parasitology , Female , Skin/parasitology , Leishmaniasis, Visceral/drug therapy , Middle Aged , Young Adult , Amphotericin B/pharmacokinetics , Amphotericin B/therapeutic use , Amphotericin B/administration & dosage , Adolescent , Asia, SouthernABSTRACT
IKZF1-deletions occur in 10-15% of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and predict a poor outcome. However, the impact of IKZF1-loss on sensitivity to drugs used in contemporary treatment protocols has remained underexplored. Here we show in experimental models and in patients that loss of IKZF1 promotes resistance to AraC, a key component of both upfront and relapsed treatment protocols. We attribute this resistance, in part, to diminished import and incorporation of cytarabine (AraC) due to reduced expression of the solute carrier hENT1. Moreover, we find elevated mRNA expression of Evi1, a known driver of therapy resistance in myeloid malignancies. Finally, a kinase directed CRISPR/Cas9-screen identified that inhibition of either mediator kinases CDK8/19 or casein kinase 2 can restore response to AraC. We conclude that this high-risk patient group could benefit from alternative antimetabolites, or targeted therapies that resensitize the cells to AraC.
ABSTRACT
BACKGROUND: Graft-versus-host disease (GvHD) and rejection are main limitations of cord blood transplantation (CBT), more so in patients with severe inflammation or previous rejections. While rigorous T-cell depletion with antithymocyte globulin (ATG) is needed to prevent GvHD and rejection, overexposure to ATG leads to slow T-cell recovery after transplantation, especially in CBT. OBJECTIVE: To evaluate high-dose, upfront ATG with individualized dosing and therapeutic drug monitoring (TDM) in pediatric CBT for patients at high risk for GvHD and rejection. STUDY DESIGN: Heavily inflamed patients and patients with a recent history of rejection were eligible for individualized high-dose ATG with real-time TDM. The ATG dosing scheme was adjusted to target a post-CBT exposure of <10 AU*day/mL, while achieving a pre-CBT exposure of 60-120 AU*day/mL; exposure levels previously defined for optimal efficacy and safety in terms of reduced GvHD and rejection, respectively. Main outcomes of interest included efficacy (target exposure attainment) and safety (incidence of GvHD and rejection). Other outcomes of interest included T-cell recovery and survival. RESULTS: Twenty-one patients were included ranging from 2 months to 18 years old, receiving an actual median cumulative dose of ATG of 13.3 mg/kg (range 6-30 mg/kg) starting at a median 15 days (range 12-17) prior to CBT. Dosing was adjusted in 14 patients (increased in 3 and decreased in 11 patients). Eighteen (86%) and 19 (91%) patients reached the target pre-CBT and post-CBT exposure, respectively. Cumulative incidence for acute GvHD was 34% (95% CI 23-45) and 5% (95% CI 0-10%) for grade 2-4 and grade 3-4, respectively; cumulative incidence of rejection was 9% (95% CI 2-16%). Overall survival was 75% (95% CI 65-85%). CONCLUSION: Individualized high-dose ATG with TDM is feasible and safe for patients with hyperinflammation in a CBT setting. We observe high target ATG exposure attainment, good immune reconstitution (despite very high doses of ATG) and acceptable rates of GvHD and rejection.
Subject(s)
Antilymphocyte Serum , Cord Blood Stem Cell Transplantation , Drug Monitoring , Graft vs Host Disease , Humans , Antilymphocyte Serum/administration & dosage , Antilymphocyte Serum/therapeutic use , Child , Graft vs Host Disease/drug therapy , Graft vs Host Disease/prevention & control , Male , Female , Cord Blood Stem Cell Transplantation/methods , Adolescent , Child, Preschool , Drug Monitoring/methods , Infant , Graft Rejection/drug therapy , T-Lymphocytes/immunology , Immunosuppressive Agents/therapeutic use , Immunosuppressive Agents/administration & dosageABSTRACT
AIMS: Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. METHODS: This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. RESULTS: Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10-6). CONCLUSIONS: While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.
ABSTRACT
BACKGROUND: PEGasparaginase is known to be a critical drug for treating pediatric acute lymphoblastic leukemia (ALL), however, there is insufficient evidence to determine the optimal dose for infants who are less than one year of age at diagnosis. This international study was conducted to identify the pharmacokinetics of PEGasparaginase in infants with newly diagnosed ALL and gather insight into the clearance and dosing of this population. METHODS: Infants with ALL who received treatment with PEGasparaginase were included in our population pharmacokinetic assessment employing non-linear mixed effects modelling (NONMEM). RESULTS: 68 infants with ALL, with a total of 388 asparaginase activity samples, were included. PEGasparaginase doses ranging from 400 to 3,663 IU/m2 were administered either intravenously or intramuscularly. A one-compartment model with time-dependent clearance, modeled using a transit model, provided the best fit to the data. Body weight was significantly correlated with clearance and volume of distribution. The final model estimated a half-life of 11.7 days just after administration, which decreased to 1.8 days 14 days after administration. Clearance was 19.5% lower during the post-induction treatment phase compared to induction. CONCLUSION: The pharmacokinetics of PEGasparaginase in infants diagnosed under one year of age with ALL is comparable to that of older children (1-18 years). We recommend a PEGasparaginase dosing at 1,500 IU/m2 for infants without dose adaptations according to age, and implementing therapeutic drug monitoring as standard practice.
Subject(s)
Antineoplastic Agents , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Child , Infant , Humans , Adolescent , Child, Preschool , Asparaginase/pharmacokinetics , Asparaginase/therapeutic use , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Drug MonitoringABSTRACT
BACKGROUND: Volumetric Absorptive Microsampling (VAMS) is a useful tool for therapeutic drug monitoring (TDM) of oral targeted anticancer agents. VAMS aims to improve safety and efficacy by enabling at-home blood sample collection by patients. This study aimed to develop and validate an ultra-high performance liquid chromatography-tandem mass spectrometry method for the quantitative determination of abiraterone, alectinib, cabozantinib, imatinib, olaparib, sunitinib, and the metabolites, Δ(4)-abiraterone (D4A), alectinib-M4, imatinib-M1, and N -desethyl sunitinib, in dried whole blood samples using VAMS to support TDM. METHODS: After the collection of 10 µL of whole blood sample using the VAMS device, the analytes were extracted from the tip using methanol with shaking, evaporated, and reconstituted in acetonitrile:0.1 mol/L ammonium hydroxide in water (1:1, vol/vol). The extracts were then analyzed using ultra-high performance liquid chromatography-tandem mass spectrometry. Validation experiments based on the ICH M10 guideline were carried out, and stability was evaluated under shipping and storage conditions. VAMS specimens were collected in the outpatient clinic to demonstrate the applicability of the assay. RESULTS: The validated range of the method was considered accurate and precise for all analytes. Accordingly, the validation experiments met the relevant requirements, except for cross-analyte interference. Based on the stability data, shipment can be performed at room temperature within 14 days after sample collection and the VAMS specimen can be stored up to 9 months at -20 and -70°C. Samples from 59 patients were collected at the hospital. CONCLUSIONS: The developed method could be used to successfully quantify the concentrations of abiraterone, D4A, alectinib, alectinib-M4, cabozantinib, imatinib, imatinib-M1, olaparib, sunitinib, and N -desethyl sunitinib within the validated range using VAMS. Therefore, the method can be used to estimate the dried whole blood-to-plasma ratios for TDM in the clinic.
Subject(s)
Antineoplastic Agents , Drug Monitoring , Tandem Mass Spectrometry , Humans , Drug Monitoring/methods , Antineoplastic Agents/blood , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Tandem Mass Spectrometry/methods , Chromatography, High Pressure Liquid/methods , Administration, Oral , Dried Blood Spot Testing/methods , Imatinib Mesylate/blood , Imatinib Mesylate/pharmacokineticsABSTRACT
BACKGROUND: the study aims to evaluate whether high plasma trough levels of the kinase inhibitors (K.I.s) crizotinib, alectinib, osimertinib, dabrafenib, and trametinib were associated with a higher risk of toxicity in non-small-cell lung cancer patients. METHODS: In this retrospective cohort study, patients with non-small-cell lung cancer treated with the selected K.I.s were included if at least one plasma trough level at steady state (C min,ss ) was available. Data were extracted from electronic medical records and laboratory databases. The high group for each K.I. was defined as 10% of patients with the highest first C min,ss . The remaining patients were placed in the non-high group. The frequency of dose-limiting toxicities (DLTs), defined as adverse events leading to dose reduction, dose interruption, or permanent discontinuation, was compared between the 2 groups. RESULTS: A total of 542 patients were included in the different K.I. groups. A high C min,ss of crizotinib (n = 96), alectinib (n = 105), osimertinib (n = 227), dabrafenib (n = 52), and trametinib (n = 62) correlated with a C min,ss ≥490, ≥870, ≥405, ≥150, and ≥25 ng/mL, respectively. DLTs were more common in the alectinib high group than in the alectinib non-high group (64% vs. 29%, P = 0.036). Liver toxicity was observed in 4 (36%) patients in the high group and 5 (5%) patients in the non-high group ( P = 0.007). For other K.I.s, no significant differences were observed in the frequency of DLTs between the high and non-high groups. CONCLUSIONS: For alectinib, high C min,ss was correlated with a higher risk of DLT. No differences in the frequency of DLTs were observed between the high and non-high groups for crizotinib, osimertinib, dabrafenib, and trametinib.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Crizotinib/therapeutic use , Lung Neoplasms/drug therapy , Retrospective Studies , Clinical Relevance , Anaplastic Lymphoma Kinase/therapeutic use , Protein Kinase Inhibitors/adverse effectsABSTRACT
BACKGROUND: Tocilizumab in the treatment of rheumatoid arthritis (RA) is a potential candidate for concentration-guided tapering because the standard dose of tocilizumab results in a wide range of serum concentrations, usually above the presumed therapeutic window, and an exposure-response relationship has been described. However, no clinical trials have been published to date on this subject. Therefore, the objective of this study was to assess the feasibility of the tapering of intravenous (iv) tocilizumab with the use of a pharmacokinetic model-based algorithm in RA patients. METHODS: A randomized controlled trial with a double-blind design and follow-up of 24 weeks was conducted. RA patients who received the standard of tocilizumab for at least the past 24 weeks, which is 8 mg/kg every 4 weeks, were included. Patients with a tocilizumab serum concentration above 5 mg/L at trough were randomized between concentration-guided dose tapering, referred to as therapeutic drug monitoring (TDM), or the standard 8 mg/kg dose. In the TDM group, the tocilizumab dose was tapered with a recently published model-based algorithm to achieve a target concentration of 4-6 mg/L after 20 weeks of dose tapering. RESULTS: Twelve RA patients were included and 10 were randomized between the TDM and standard dose group. The study was feasible regarding the predefined feasibility criteria and patients had a positive attitude toward therapeutic drug monitoring. In the TDM group, the tocilizumab trough concentration within patients decreased on average by 24.5 ± 18.3 mg/L compared with a decrease of 2.8 ± 12 mg/L in the standard dose group. None of the patients in the TDM group reached the drug range of 4-6 mg/L. Instead, tocilizumab concentrations of 1.6 and 1.5 mg/L were found for the 2 patients who completed follow-up on the tapered dose. No differences in RA disease activity were observed between the 2 study groups. CONCLUSIONS: This study was the first to show that it is feasible to apply a dose-reduction algorithm based on a pharmacokinetic model in clinical practice. However, the current algorithm needs to be optimized before it can be applied on a larger scale.
Subject(s)
Algorithms , Antibodies, Monoclonal, Humanized , Arthritis, Rheumatoid , Drug Monitoring , Humans , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Arthritis, Rheumatoid/drug therapy , Double-Blind Method , Female , Middle Aged , Male , Drug Monitoring/methods , Antirheumatic Agents/administration & dosage , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/therapeutic use , Antirheumatic Agents/blood , Drug Tapering/methods , Feasibility Studies , Dose-Response Relationship, Drug , Aged , AdultABSTRACT
The low incidence of vincristine-induced peripheral neuropathy (VIPN) in Kenyan children may result from low vincristine exposure. We studied vincristine exposure in Kenyan children and dose-escalated in case of low vincristine exposure (NCT05844670). Average vincristine exposure was high. Individual vincristine exposure was assessed with a previously developed nomogram. A 20% dose increase was recommended for participants with low exposure and no VIPN, hyperbilirubinemia, or malnutrition. None of the 15 participants developed VIPN. Low vincristine exposure was seen in one participant: a dose increase was implemented without side effects. In conclusion, the participants did not develop VIPN despite having high vincristine exposure.
Subject(s)
Feasibility Studies , Peripheral Nervous System Diseases , Vincristine , Humans , Vincristine/adverse effects , Vincristine/administration & dosage , Female , Male , Kenya , Child, Preschool , Child , Peripheral Nervous System Diseases/chemically induced , Infant , Antineoplastic Agents, Phytogenic/adverse effects , Antineoplastic Agents, Phytogenic/administration & dosage , Neoplasms/drug therapy , Follow-Up Studies , AdolescentABSTRACT
OBJECTIVES: To improve visceral leishmaniasis (VL) treatment in Eastern Africa, 14- and 28-day combination regimens of paromomycin plus allometrically dosed miltefosine were evaluated. As the majority of patients affected by VL are children, adequate paediatric exposure to miltefosine and paromomycin is key to ensuring good treatment response. METHODS: Pharmacokinetic data were collected in a multicentre randomized controlled trial in VL patients from Kenya, Sudan, Ethiopia and Uganda. Patients received paromomycin (20 mg/kg/day for 14 days) plus miltefosine (allometric dose for 14 or 28 days). Population pharmacokinetic models were developed. Adequacy of exposure and target attainment of paromomycin and miltefosine were evaluated in children and adults. RESULTS: Data from 265 patients (59% ≤12 years) were available for this pharmacokinetic analysis. Paromomycin exposure was lower in paediatric patients compared with adults [median (IQR) end-of-treatment AUC0-24h 187 (162-203) and 242 (217-328) µg·h/mL, respectively], but were both within the IQR of end-of-treatment exposure in Kenyan and Sudanese adult patients from a previous study. Cumulative miltefosine end-of-treatment exposure in paediatric patients and adults [AUCD0-28 517 (464-552) and 524 (456-567) µg·day/mL, respectively] and target attainment [time above the in vitro susceptibility value EC90 27 (25-28) and 30 (28-32) days, respectively] were comparable to previously observed values in adults. CONCLUSIONS: Paromomycin and miltefosine exposure in this new combination regimen corresponded to the desirable levels of exposure, supporting the implementation of the shortened 14 day combination regimen. Moreover, the lack of a clear exposure-response and exposure-toxicity relationship indicated adequate exposure within the therapeutic range in the studied population, including paediatric patients.
Subject(s)
Antiprotozoal Agents , Leishmaniasis, Visceral , Humans , Adult , Child , Paromomycin/therapeutic use , Leishmaniasis, Visceral/drug therapy , Antiprotozoal Agents/pharmacokinetics , Kenya , Phosphorylcholine/therapeutic use , Phosphorylcholine/pharmacokinetics , Uganda , Treatment OutcomeABSTRACT
OBJECTIVE: In the first part of this phase II study (NCT01164995), the combination of carboplatin and adavosertib (AZD1775) was shown to be safe and effective in patients with TP53 mutated platinum-resistant ovarian cancer (PROC). Here, we present the results of an additional safety and efficacy cohort and explore predictive biomarkers for resistance and response to this combination treatment. METHODS: This is a phase II, open-label, non-randomized study. Patients with TP53 mutated PROC received carboplatin AUC 5 mg/ ml·min intravenously and adavosertib 225 mg BID orally for 2.5 days in a 21-day cycle. The primary objective is to determine the efficacy and safety of carboplatin and adavosertib. Secondary objectives include progression-free survival (PFS), changes in circulating tumor cells (CTC) and exploration of genomic alterations. RESULTS: Thirty-two patients with a median age of 63 years (39-77 years) were enrolled and received treatment. Twenty-nine patients were evaluable for efficacy. Bone marrow toxicity, nausea and vomiting were the most common adverse events. Twelve patients showed partial response (PR) as best response, resulting in an objective ORR of 41% in the evaluable patients (95% CI: 23%-61%). The median PFS was 5.6 months (95% CI: 3.8-10.3). In patients with tumors harboring CCNE1 amplification, treatment efficacy was slightly but not significantly better. CONCLUSIONS: Adavosertib 225 mg BID for 2.5 days and carboplatin AUC 5 could be safely combined and showed anti-tumor efficacy in patients with PROC. However, bone marrow toxicity remains a point of concern, since this is the most common reason for dose reductions and dose delays.
Subject(s)
Ovarian Neoplasms , Female , Humans , Middle Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers , Carboplatin/therapeutic use , Carcinoma, Ovarian Epithelial/drug therapy , Cell Cycle Proteins/genetics , Disease-Free Survival , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Protein-Tyrosine Kinases/antagonists & inhibitors , Tumor Suppressor Protein p53/genetics , Adult , AgedABSTRACT
BACKGROUND: Prolonging the time which plasma concentrations of antimitotic drugs, such as the taxanes, exceed cytotoxic threshold levels may be beneficial for their efficacy. Orally administered docetaxel offers an undemanding approach to optimize such time above threshold plasma concentrations (t C>threshold ). METHODS: A nonsystematic literature screen was performed to identify studies reporting in-vitro half-maximal inhibitory concentration (IC 50 ) values for docetaxel. Pharmacokinetics of intravenously (i.v.) docetaxel (75 mg/m 2 ) and orally administered docetaxel (ModraDoc006) co-administered with ritonavir (r) given twice daily (30 + 20 mg concomitant with 100 mg ritonavir bis in die) were simulated using previously developed population models. T C>threshold was calculated for a range of relevant thresholds in terms of in-vitro cytotoxicity and plasma concentrations achieved after i.v. and oral administration of docetaxel. A published tumor growth inhibition model for i.v. docetaxel was adapted to predict the effect of attainment of time above threshold levels on tumor dynamics. RESULTS: Identified studies reported a wide range of in vitro IC 50 values [median 0.04 µmol/L, interquartile range (IQR): 0.0046-0.62]. At cytotoxic thresholds <0.078 µmol/L oral docetaxel shows up to ~7.5-fold longer t C>threshold within each 3-week cycle for a median patient compared to i.v.. Simulations of tumor dynamics showed the increased relative potential of oral docetaxel for inhibition of tumor growth at thresholds of 0.075, 0.05 and 0.005 µmol/L. CONCLUSION: ModraDoc006/r is superior to i.v. docetaxel 75 mg/m 2 in terms of median time above cytotoxic threshold levels <0.078 µmol/L. This may indicate superior cytotoxicity and inhibition of tumor growth compared to i.v. administration for relatively docetaxel-sensitive tumors.
Subject(s)
Antimitotic Agents , Antineoplastic Agents , Breast Neoplasms , Humans , Female , Docetaxel , Breast Neoplasms/pathology , Ritonavir , Antineoplastic Agents/pharmacology , Taxoids , Administration, OralABSTRACT
PURPOSE: Pemetrexed is a cytotoxic drug used for the treatment of lung cancer and mesothelioma. The use of a low test dosing of cytotoxic drugs may aid in dose individualization without causing harm. The aim of this proof-of-concept study was to assess if the pharmacokinetics (PKs) of a test dose could predict the PKs of a therapeutic pemetrexed dose. METHODS: Ten patients received both a low test dose (100 µg) and a therapeutic dose of pemetrexed after which plasma concentrations pemetrexed were measured. PK analysis was performed by means of nonlinear mixed-effects modelling. The predictive performances of test dose clearance and renal function towards a therapeutic dose were assessed. RESULTS: The PKs of a pemetrexed test dose were best described by a one-compartment model with linear elimination. A high variability in the administered dose was observed for the test dose, but not for the therapeutic dose. A statistically significant correlation between test dose clearance and therapeutic dose clearance was observed (Spearman's rho: 0.758, P = 0.02). The predictive performance of test dose clearance was worse than renal function: mean predictive error (+95% confidence interval [CI]) 53.9% (50.1-57.6%) vs 19.4% (12.4-26.4%) and normalized root-mean square error (+95% CI) 57.8% (30.5-85.1%) vs 25.7% (20.3-31.0%). CONCLUSION: We show that test dosing of pemetrexed is feasible, but there seems no added value for a low test dosing in the dose individualization of pemetrexed.
Subject(s)
Antineoplastic Agents , Lung Neoplasms , Humans , Pemetrexed/adverse effects , Pemetrexed/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Lung Neoplasms/drug therapyABSTRACT
AIMS: Carboplatin is generally dosed based on a modified Calvert formula, in which the Cockcroft-Gault-based creatinine clearance (CRCL) is used as proxy for the glomerular filtration rate (GFR). The Cockcroft-Gault formula (CG) overpredicts CRCL in patients with an aberrant body composition. The CT-enhanced estimate of RenAl FuncTion (CRAFT) was developed to compensate for this overprediction. We aimed to evaluate whether carboplatin clearance is better predicted by CRCL based on the CRAFT compared to the CG. METHODS: Data of four previously conducted trials was used. The CRAFT was divided by serum creatinine to derive CRCL. The difference between CRAFT- and CG-based CRCL was assessed by population pharmacokinetic modelling. Furthermore, the difference in calculated carboplatin dose was assessed in a heterogeneous dataset. RESULTS: In total, 108 patients were included in the analysis. Addition of the CRAFT- and CG-based CRCL as covariate on carboplatin clearance led, respectively, to an improved model fit with a 26-point drop in objective function value and a worsened model fit with an increase of 8 points. In 19 subjects with serum creatinine <50 µmol/L, the calculated carboplatin dose was 233 mg higher using the CG. CONCLUSIONS: Carboplatin clearance is better predicted by CRAFT vs. CG-based CRCL. In subjects with low serum creatinine, the calculated carboplatin dose using CG exceeds the dose using CRAFT, which might explain the need for dose capping when using the CG. Therefore, the CRAFT might be an alternative for dose capping while still dosing accurately.
Subject(s)
Antineoplastic Agents , Humans , Carboplatin , Creatinine , Glomerular Filtration Rate , Kidney/physiology , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: Olaparib is given in a fixed dose of twice-daily 300 mg in patients who are diagnosed with ovarian cancer, breast cancer, prostate cancer or pancreas cancer and has a high interpatient variability in pharmacokinetic exposure. The objective of this study was to investigate whether pharmacokinetic exposure of olaparib is related to efficacy and safety in a real-life patient' cohort. METHODS: A longitudinal observational study was conducted in patients who received olaparib for metastatic ovarian cancer of whom pharmacokinetic samples were collected. A Kaplan-Meier analyses was used to explore the relationship between olaparib exposure, measured as (calculated) minimum plasma concentrations (Cmin), and efficacy, Univariate and multivariate cox-regression analyses were performed. Also, the Cmin of patients who experienced toxicity was compared with patients who did not experience any toxicity. RESULTS: Thirty-five patients were included in the exposure-efficacy analyses, with a median olaparib Cmin of 1514 ng/mL. There was no statistical significant difference in PFS of patients below and above the median Cmin concentration of olaparib, with a hazard ratio of 1.06 (95% confidence interval: 0.46-2.45, p = 0.9)). For seven patients pharmacokinetic samples were available before toxicity occurred, these patients had a higher Cmin of olaparib in comparison with patients who had not experienced any toxicity (n = 33), but it was not statistically significant (p = 0.069). CONCLUSIONS: Our study shows that exposure of olaparib is not related to PFS. This suggests that the approved dose of olaparib yields sufficient target inhibition in the majority of patients.
Subject(s)
Ovarian Neoplasms , Male , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Phthalazines/adverse effects , Piperazines/adverse effects , Kaplan-Meier EstimateABSTRACT
BACKGROUND: Abiraterone acetate is an irreversible 17α-hydroxylase/C17, 20-lyase (CYP17) inhibitor approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC) patients. Inhibition of this enzyme leads to low testosterone and cortisol levels in blood. There is growing evidence that clinical efficacy of abiraterone is related to the rate of suppression of serum testosterone. However, quantification of very low levels of circulating testosterone is challenging. We therefore aimed to investigate whether circulating cortisol levels could be used as a surrogate biomarker for CYP17 inhibition in patients with mCRPC treated with abiraterone acetate. PATIENTS AND METHODS: mCRPC patients treated with abiraterone acetate were included. Abiraterone and cortisol levels were measured with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). On treatment cortisol and abiraterone concentrations were related to treatment response and progression free survival. RESULTS: In total 117 patients were included with a median cortisol concentration of 1.13 ng/ml (range: 0.03 - 82.2) and median abiraterone trough concentration (Cmin) of 10.2 ng/ml (range: 0.58 - 92.1). In the survival analyses, abiraterone Cmin ≥ 8.4 ng/mL and cortisol < 2.24 ng/mL were associated with a longer prostate-specific antigen (PSA) independent progression-free survival than patients with an abiraterone concentration ≥ 8.4 ng/mL and a cortisol concentration ≥ 2.24 ng/mL (13.8 months vs. 3.7 months). CONCLUSION: Our study shows that cortisol is not an independent predictor of abiraterone response in patients with mCRPC, but it is of added value in combination with abiraterone levels, to predict a response on abiraterone.
Subject(s)
Abiraterone Acetate , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Abiraterone Acetate/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Hydrocortisone , Steroid 17-alpha-Hydroxylase , Chromatography, Liquid , Tandem Mass Spectrometry , Treatment Outcome , Prostate-Specific Antigen/therapeutic use , Testosterone/therapeutic useABSTRACT
BACKGROUND: Therapeutic drug monitoring of mesalazine (5-ASA) in patients with ulcerative colitis is unavailable. Mucosal 5-ASA concentrations are assumed to be higher during remission, but biopsy is not practical. Therefore, we investigated the feasibility of measuring mesalazine levels in feces. To explore the potential role of fecal mesalazine measurements in therapeutic drug monitoring, we compared the dry fecal concentration and daily fecal excretion of 5-ASA and its metabolite N-acetyl-5-ASA in patients with ulcerative colitis with active and quiescent disease. METHODS: Adults with ulcerative colitis on oral mesalazine and scheduled for colonoscopy were eligible for inclusion in this cross-sectional study. Stool and urine samples were collected for 48 and 24 hours, respectively, and rectal biopsies were performed. (N-acetyl-)5-ASA was measured using mass spectrometry. Biochemically active disease was defined as a fecal calprotectin level above 100 mcg/g and endoscopically active disease as any activity following the endoscopic Mayo score (≥1). RESULTS: Approximately 28 patients were included in the study. Daily fecal excretion of (N-acetyl-)5-ASA did not differ between patients with (n = 13) and without (n = 15) endoscopically active disease [median 572 mg/d versus 597 mg/d ( P = 0.86) for 5-ASA and 572 mg/d versus 554 mg/d ( P = 0.86) for N-acetyl-5-ASA]. The same applied to the fecal concentration [median 9.7 mcg/mg dry weight versus 10.3 ( P = 0.53) and 12.0 versus 9.9 ( P = 0.89)]. The results were comparable when the biochemical disease activity definition was used. The mucosal concentrations and urinary excretion of (N-acetyl-)5-ASA did not differentiate between quiescent and active activity. CONCLUSIONS: Fecal (N-acetyl-)5-ASA measurements do not correlate with disease activity, which renders it an unsuitable tool for therapeutic drug monitoring of mesalazine.