The cycle effect quantified: reduced tumour uptake in subsequent cycles of [177Lu]Lu-HA-DOTATATE during peptide receptor radionuclide therapy.

BACKGROUND: Clear evidence regarding the effect of reduced tumour accumulation in later peptide receptor radionuclide therapy (PRRT) cycles is lacking. Therefore, we aimed to quantify potential cycle effects for patients treated with [177Lu]Lu-HA-DOTATATE using a population pharmacokinetic (PK) modelling approach. METHODS: A population PK model was developed using imaging data from 48 patients who received multiple cycles of [177Lu]Lu-HA-DOTATATE. The five-compartment model included a central, kidney, spleen, tumour and lumped rest compartment. Tumour volume and continued use of long-acting somatostatin analogues (SSAs) were tested as covariates in the model. In addition, the presence of a cycle effect was evaluated by relating the uptake rate in a specific cycle as a fraction of the (tumour or organ) uptake rate in the first cycle. RESULTS: The final PK model adequately captured observed radioactivity accumulation in kidney, spleen and tumour. A higher tumour volume was identified to increase the tumour uptake rate, where a twofold increase in tumour volume resulted in a 2.3-fold higher uptake rate. Also, continued use of long-acting SSAs significantly reduced the spleen uptake rate (68.4% uptake compared to SSA withdrawal (10.5% RSE)). Lastly, a cycle effect was significantly identified, where tumour uptake rate decreased to 86.9% (5.3% RSE) in the second cycle and even further to 79.7% (5.6% RSE) and 77.6% (6.2% RSE) in the third and fourth cycle, respectively, compared to cycle one. CONCLUSIONS: Using a population PK modelling approach, the cycle effect of reduced tumour uptake in subsequent PRRT cycles was quantified. Our findings implied that downregulation of target receptors is probably not the major cause of the cycle effect, due to a plateau in the decrease of tumour uptake in the fourth cycle.

The use of microtracers in food-effect trials: An alternative study design for toxic drugs with long half-lives exemplified by the case for alectinib.

The traditional design of food-effect studies has a high patient burden for toxic drugs with long half-lives (e.g., anticancer agents). Microtracers could be used to assess food-effect in patients without influencing their ongoing treatment. The feasibility of a microtracer food-effect study during steady-state of the therapeutic drug was investigated in an in silico simulation study with alectinib as an example for a relative toxic drug with a long half-life. Microtracer pharmacokinetics were simulated based on a previously published population pharmacokinetic model and used for estimation of a model with and a model without food as a covariate on oral bioavailability of alectinib (assuming a 40% food-effect). Power was defined as the fraction of clinical trials where a significant (p < 0.01) food-effect was identified. The proposed study design of 10 patients on steady-state treatment, 10 blood samples collected within 24 h after administration and an assumed food-effect of 40% had a power of 99.9%. The mean estimated food-effect was 39.8% (80% confidence interval: 31.0%-48.6%). The feasibility of microtracer food-effect studies was demonstrated. The design of the microtracer food-effect study allowed estimation of the food-effect with minimal influence on therapeutic treatment and reducing patient burden compared to the traditional study design for toxic drugs with long half-lives.

Semi-physiological Enriched Population Pharmacokinetic Modelling to Predict the Effects of Pregnancy on the Pharmacokinetics of Cytotoxic Drugs.

BACKGROUND AND OBJECTIVE: As a result of changes in physiology during pregnancy, the pharmacokinetics (PK) of drugs can be altered. It is unclear whether under- or overexposure occurs in pregnant cancer patients and thus also whether adjustments in dosing regimens are required. Given the severity of the malignant disease and the potentially high impact on both the mother and child, there is a high unmet medical need for adequate and tolerable treatment of this patient population. We aimed to develop and evaluate a semi-physiological enriched model that incorporates physiological changes during pregnancy into available population PK models developed from non-pregnant patient data. METHODS: Gestational changes in plasma protein levels, renal function, hepatic function, plasma volume, extracellular water and total body water were implemented in existing empirical PK models for docetaxel, paclitaxel, epirubicin and doxorubicin. These models were used to predict PK profiles for pregnant patients, which were compared with observed data obtained from pregnant patients. RESULTS: The observed PK profiles were well described by the model. For docetaxel, paclitaxel and doxorubicin, an overprediction of the lower concentrations was observed, most likely as a result of a lack of data on the gestational changes in metabolizing enzymes. For paclitaxel, epirubicin and doxorubicin, the semi-physiological enriched model performed better in predicting PK in pregnant patients compared with a model that was not adjusted for pregnancy-induced changes. CONCLUSION: By incorporating gestational changes into existing population pharmacokinetic models, it is possible to adequately predict plasma concentrations of drugs in pregnant patients which may inform dose adjustments in this population.

Radiosensitisation by olaparib through focused ultrasound delivery in a diffuse midline glioma model.

BACKGROUND AND PURPOSE: Diffuse midline glioma H3K27-altered (DMG) is an aggressive, inoperable, predominantly paediatric brain tumour. Treatment strategies are limited, resulting in a median survival of only 11 months. Currently, radiotherapy (RT), often combined with temozolomide, is considered the standard of care but remains palliative, highlighting the urgency for new therapies. Radiosensitisation by olaparib, an inhibitor of PARP1 and subsequently PAR-synthesis, is a promising treatment option. We assessed whether PARP1 inhibition enhances radiosensitivity in vitro and in vivo following focused ultrasound mediated blood-brain barrier opening (FUS-BBBO). METHODS: Effects of PARP1 inhibition were evaluated in vitro using viability, clonogenic, and neurosphere assays. In vivo olaparib extravasation and pharmacokinetic profiling following FUS-BBBO was measured by LC-MS/MS. Survival benefit of FUS-BBBO combined with olaparib and RT was assessed using a patient-derived xenograft (PDX) DMG mouse model. RESULTS: Treatment with olaparib in combination with radiation delayed tumour cell proliferation in vitro through the reduction of PAR. Prolonged exposure of low olaparib concentration was more efficient in delaying cell growth than short exposure of high concentration. FUS-BBBO increased olaparib bioavailability in the pons by 5.36-fold without observable adverse effects. A Cmax of 54.09 µM in blood and 1.39 µM in the pontine region was achieved following administration of 100 mg/kg olaparib. Although RT combined with FUS-BBBO mediated olaparib extravasation delayed local tumour growth, survival benefits were not observed in an in vivo DMG PDX model. CONCLUSIONS: Olaparib effectively radiosensitises DMG cells in vitro and reduces primary tumour growth in vivo when combined with RT. Further studies are needed to investigate the therapeutic benefit of olaparib in suitable preclinical PDX models.

Exposure-response analyses of BRAF- and MEK-inhibitors dabrafenib plus trametinib in melanoma patients.

INTRODUCTION: Dabrafenib and trametinib are currently administered at fixed doses, at which interpatient variability in exposure is high. The aim of this study was to investigate whether drug exposure is related to efficacy and toxicity in a real-life cohort of melanoma patients treated with dabrafenib plus trametinib. PATIENTS AND METHODS: An observational study was performed in which pharmacokinetic samples were collected as routine care. Using estimated dabrafenib Area Under the concentration-time Curve and trametinib trough concentrations (Cmin), univariable and multivariable exposure-response analyses were performed. RESULTS: In total, 140 patients were included. Dabrafenib exposure was not related to either progression-free survival (PFS) or overall survival (OS). Trametinib exposure was related to survival, with Cmin ≥ 15.6 ng/mL being identified as the optimal threshold. Median OS was significantly longer in patients with trametinib Cmin ≥ 15.6 ng/mL (22.8 vs. 12.6 months, P = 0.003), with a multivariable hazard ratio of 0.55 (95% CI 0.36-0.85, P = 0.007). Median PFS in patients with trametinib Cmin levels ≥ 15.6 ng/mL (37%) was 10.9 months, compared with 6.0 months for those with Cmin below this threshold (P = 0.06). Multivariable analysis resulted in a hazard ratio of 0.70 (95% CI 0.47-1.05, P = 0.082). Exposure to dabrafenib and trametinib was not related to clinically relevant toxicities. CONCLUSIONS: Overall survival of metastasized melanoma patients with trametinib Cmin levels ≥ 15.6 ng/mL is ten months longer compared to patients with Cmin below this threshold. This would theoretically provide a rationale for therapeutic drug monitoring of trametinib. Although a high proportion of patients are underexposed, there is very little scope for dose increments due to the risk of serious toxicity.

Therapeutic drug monitoring-based precision dosing of oral targeted therapies in oncology: a prospective multicenter study.

BACKGROUND: Oral targeted therapies show a high pharmacokinetic (PK) interpatient variability. Even though exposure has been positively correlated with efficacy for many of these drugs, these are still dosed using a one-size-fits-all approach. Consequently, individuals have a high probability to be either underexposed or overexposed, potentially leading to suboptimal outcomes. Therapeutic drug monitoring, which is personalized dosing based on measured systemic drug concentrations, could address these problems. PATIENTS AND METHODS: Patients were enrolled in this prospective multicenter study (www.trialregister.nl; NL6695) if they started treatment with one of the 24 participating oral targeted therapies. Primary outcome was to halve the proportion of underexposed patients, compared with historical data. PK sampling was carried out after 4, 8 and 12 weeks, and every 12 weeks thereafter. In case of Cmin below the predefined target and manageable toxicity, a pharmacokinetically guided intervention was proposed (i.e. checking compliance and drug-drug interactions, concomitant intake with food, splitting intake moments or dose increments). RESULTS: In total, 600 patients were included of whom 426 patients are assessable for the primary outcome and 552 patients had ≥1 PK sample(s) available and were therefore assessable for the overall analyses. Pharmacokinetically guided dosing reduced the proportion of underexposed patients at the third PK measurement by 39.0% (95% confidence interval 28.0% to 49.0%) compared with historical data. At the third PK measurement, 110 out of 426 patients (25.8%) had a low exposure. In total, 294 patients (53.3%) had ≥1 PK sample(s) below the preset target at a certain time point during treatment. In 166 of these patients (56.5%), pharmacokinetically guided interventions were carried out, which were successful in 113 out of 152 assessable patients (74.3%). CONCLUSIONS: Pharmacokinetically guided dose optimization of oral targeted therapies was feasible in clinical practice and reduced the proportion of underexposed patients considerably.

Deep learning body-composition analysis of clinically acquired CT-scans estimates creatinine excretion with high accuracy in patients and healthy individuals.

Assessment of daily creatinine production and excretion plays a crucial role in the estimation of renal function. Creatinine excretion is estimated by creatinine excretion equations and implicitly in eGFR equations like MDRD and CKD-EPI. These equations are however unreliable in patients with aberrant body composition. In this study we developed and validated equations estimating creatinine production using deep learning body-composition analysis of clinically acquired CT-scans. We retrospectively included patients in our center that received any CT-scan including the abdomen and had a 24-h urine collection within 2 weeks of the scan (n = 636). To validate the equations in healthy individuals, we included a kidney donor dataset (n = 287). We used a deep learning algorithm to segment muscle and fat at the 3rd lumbar vertebra, calculate surface areas and extract radiomics parameters. Two equations for CT-based estimate of RenAl FuncTion (CRAFT 1 including CT parameters, age, weight, and stature and CRAFT 2 excluding weight and stature) were developed and compared to the Cockcroft-Gault and the Ix equations. CRAFT1 and CRAFT 2 were both unbiased (MPE = 0.18 and 0.16 mmol/day, respectively) and accurate (RMSE = 2.68 and 2.78 mmol/day, respectively) in the patient dataset and were more accurate than the Ix (RMSE = 3.46 mmol/day) and Cockcroft-Gault equation (RMSE = 3.52 mmol/day). In healthy kidney donors, CRAFT 1 and CRAFT 2 remained unbiased (MPE = - 0.71 and - 0.73 mmol/day respectively) and accurate (RMSE = 1.86 and 1.97 mmol/day, respectively). Deep learning-based extraction of body-composition parameters from abdominal CT-scans can be used to reliably estimate creatinine production in both patients as well as healthy individuals. The presented algorithm can improve the estimation of renal function in patients who have recently had a CT scan. The proposed methods provide an improved estimation of renal function that is fully automatic and can be readily implemented in routine clinical practice.

Efficacy and toxicity of vemurafenib and cobimetinib in relation to plasma concentrations, after administration via feeding tube in patients with BRAF-mutated thyroid cancer: a case series and review of literature.

INTRODUCTION: The combination of vemurafenib, a proto-oncogene B-Raf inhibitor (BRAFi) and cobimetinib, an inhibitor of mitogen-activated protein kinase kinase (MEKi) has shown to improve survival in patients with BRAF V600-mutated melanoma. BRAF mutations are also frequently detected driver mutations in other tumor types, including thyroid carcinoma. Since thyroid carcinoma is not a labeled indication for BRAF/MEKi, a cohort for patients with BRAF V600-mutated thyroid carcinoma was opened within the Drug Rediscovery Protocol (DRUP), a national ongoing pan-cancer multi-drug trial, in which patients receive off-label treatment with approved drugs based on their molecular tumor profile. RESULTS: Here, we present two patients with BRAF-mutated thyroid carcinoma, who were successfully treated with vemurafenib/cobimetinib administered via a feeding tube. Plasma concentrations of vemurafenib and cobimetinib were determined. A partial response was observed in both patients, but they experienced significant toxicity. CONCLUSION: Our cases show that vemurafenib/cobimetinib treatment is effective in BRAF V600-mutated thyroid carcinoma, also when administered via a feeding tube. Although serious side effects occurred in both patients, we hypothesize that this was not attributable to the administration route. Therefore, administration of vemurafenib/cobimetinib by feeding tube is feasible and effective. TRIAL REGISTRATION: Clinical trial identification: NCT02925234.

A highly sensitive bioanalytical method for the quantification of vinblastine, vincristine, vinorelbine and 4-O-deacetylvinorelbine in human plasma using LC-MS/MS.

A highly sensitive method was developed for the quantification of vinblastine, vincristine, vinorelbine, and its active metabolite 4-O-deacetylvinorelbine in human plasma using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Deuterated isotopes were used as internal standard and liquid-liquid extraction with tert-butyl methyl ether (TBME) was used for sample pre-treatment. The final extract was injected on a C18 column (50 × 2.1 mm ID, 5 µm). Gradient elution was used in combination with Reversed Phase chromatography to elute the analytes and internal standards from the column in 5 min and the API4000 triple quadrupole MS detector was operating in the positive ion mode. The calibration model, accuracy and precision, selectivity and specificity, dilution integrity, carryover, matrix factor and recovery, and stability were evaluated over a concentration range from 0.025 to 10 ng/mL for vinblastine, vinorelbine, and 4-O-deacetylvinorelbine and from 0.1 to 40 ng/mL for vincristine. The intra- and inter-assay bias and precisions were within ± 12.4% and ≤ 10.6%, respectively. This method was successfully applied to study the pharmacokinetics of vincristine in paediatrics and vinorelbine and 4-O-deacetylvinorelbine using in vivo mouse models.

Aminoglycoside- and glycopeptide-induced ototoxicity in children: a systematic review.

BACKGROUND: Ototoxicity has been reported after administration of aminoglycosides and glycopeptides. OBJECTIVES: To identify available evidence for the occurrence and determinants of aminoglycoside- and glycopeptide-related ototoxicity in children. MATERIALS AND METHODS: Systematic electronic literature searches that combined ototoxicity (hearing loss, tinnitus and/or vertigo) with intravenous aminoglycoside and/or glycopeptide administration in children were performed in PubMed, EMBASE and Cochrane Library databases. Studies with sample sizes of ≥50 children were included. The QUIPS tool and Cochrane criteria were used to assess the quality and risk of bias of included studies. RESULTS: Twenty-nine aminoglycoside-ototoxicity studies met the selection criteria (including 7 randomized controlled trials). Overall study quality was medium/low. The frequency of hearing loss within these studies ranged from 0%-57%, whereas the frequency of tinnitus and vertigo ranged between 0%-53% and 0%-79%, respectively. Two studies met the criteria on glycopeptide-induced ototoxicity and reported hearing loss frequencies of 54% and 55%. Hearing loss frequencies were higher in gentamicin-treated children compared to those treated with other aminoglycosides. In available studies aminoglycosides had most often been administered concomitantly with platinum agents, diuretics and other co-medication. CONCLUSIONS: In children the reported occurrence of aminoglycoside/glycopeptide ototoxicity highly varies and seems to depend on the diagnosis, aminoglycoside subtype and use of co-administered medication. More research is needed to investigate the prevalence and determinants of aminoglycoside/glycopeptide ototoxicity. Our results indicate that age-dependent audiological examination may be considered for children frequently treated with aminoglycosides/glycopeptides especially if combined with other ototoxic medication.

A physiologically based pharmacokinetic (PBPK) model to describe organ distribution of 68Ga-DOTATATE in patients without neuroendocrine tumors.

BACKGROUND: Physiologically based pharmacokinetic (PBPK) models combine drug-specific information with prior knowledge on the physiology and biology at the organism level. Whole-body PBPK models contain an explicit representation of the organs and tissue and are a tool to predict pharmacokinetic behavior of drugs. The aim of this study was to develop a PBPK model to describe organ distribution of 68Ga-DOTATATE in a population of patients without detectable neuroendocrine tumors (NETs). METHODS: Clinical 68Ga-DOTATATE PET/CT data from 41 patients without any detectable somatostatin receptor (SSTR) overexpressing tumors were included. Scans were performed at 45 min (range 30-60 min) after intravenous bolus injection of 68Ga-DOTATATE. Organ (spleen, liver, thyroid) and blood activity levels were derived from PET scans, and corresponding DOTATATE concentrations were calculated. A whole-body PBPK model was developed, including an internalization reaction, receptor recycling, enzymatic reaction for intracellular degradation and renal clearance. SSTR2 expression was added for several organs. Input parameters were fixed or estimated using a built-in Monte Carlo algorithm for parameter identification. RESULTS: 68Ga-DOTATATE was administered with a median peptide amount of 12.3 µg (range 8.05-16.9 µg) labeled with 92.7 MBq (range 43.4-129.9 MBq). SSTR2 amounts for spleen, liver and thyroid were estimated at 4.40, 7.80 and 0.0108 nmol, respectively. Variability in observed organ concentrations was best described by variability in SSTR2 expression and differences in administered peptide amounts. CONCLUSIONS: To conclude, biodistribution of 68Ga-DOTATATE was described with a whole-body PBPK model, where tissue distribution was mainly determined by variability in SSTR2 organ expression and differences in administered peptide amounts.

Prospective experimental treatment of colorectal cancer patients based on organoid drug responses.

BACKGROUND: Organoid technology has recently emerged as a powerful tool to assess drug sensitivity of individual patient tumors in vitro. Organoids may therefore represent a new avenue for precision medicine, as this circumvents many of the complexities associated with DNA- or transcriptional-profiling. MATERIALS AND METHODS: The SENSOR trial was a single-arm, single-center, prospective intervention trial to evaluate the feasibility of patient-derived organoids to allocate patients for treatment with off-label or investigational agents. The primary endpoint was an objective response rate of ≥20%. Patients underwent a biopsy for culture before commencing their last round standard of care. Organoids were exposed to a panel of eight drugs and patients were treated after progression on standard-of-care treatment and when a clear signal of antitumor activity was identified in vitro. RESULTS: Sixty-one patients were included and we generated 31 organoids of 54 eligible patients. Twenty-five cultures were subjected to drug screening and 19 organoids exhibited substantial responses to one or more drugs. Three patients underwent treatment with vistusertib and three with capivasertib. Despite drug sensitivity of organoids, patients did not demonstrate objective clinical responses to the recommended treatment. CONCLUSIONS: Organoid technology had limited value as a tool for precision medicine in this patient population because a large fraction of patients could not undergo treatment or because the recommended treatment did not elicit an objective response. We identified several essential parameters, such as the culture success rate, clinical deterioration of patients during standard of care, and rational design of drug panels that need to be accounted for in organoid-guided clinical studies.

Monitoring of EGFR mutations in circulating tumor DNA of non-small cell lung cancer patients treated with EGFR inhibitors.

PURPOSE: We studied EGFR mutations in circulating tumor DNA (ctDNA) and explored their role in predicting the progression-free survival (PFS) of non-small cell lung cancer (NSCLC) patients treated with erlotinib or gefitinib. METHODS: The L858R, T790M mutations and exon 19 deletions were quantified in plasma using digital droplet polymerase chain reaction (ddPCR). The dynamics of ctDNA mutations over time and relationships with PFS were explored. RESULTS: In total, 249 plasma samples (1-13 per patient) were available from 68 NSCLC patients. The T790M and L858R or exon 19 deletion were found in the ctDNA of 49 and 56% patients, respectively. The median (range) concentration in these samples were 7.3 (5.1-3688.7), 11.7 (5.1-12,393.3) and 27.9 (5.9-2896.7) copies/mL, respectively. Using local polynomial regression, the number of copies of EGFR mutations per mL increased several months prior to progression on standard response evaluation. CONCLUSION: This change was more pronounced for the driver mutations than for the resistance mutations. In conclusion, quantification of EGFR mutations in plasma ctDNA was predictive of treatment outcomes in NSCLC patients. In particular, an increase in driver mutation copy number could predict disease progression.

Systemic exposure of oxaliplatin and docetaxel in gastric cancer patients with peritonitis carcinomatosis treated with intraperitoneal hyperthermic chemotherapy.

In the PERISCOPE I study, gastric cancer patients with limited peritoneal dissemination were treated with systemic chemotherapy followed by (sub)total gastrectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with 460 mg/m2 hyperthermic oxaliplatin followed by normothermic docetaxel in escalating doses (0, 50, 75 mg/m2). In total, 25 patients completed the study protocol. Plasma samples were collected before the start of the HIPEC procedure, after oxaliplatin washing, after docetaxel washing and the following morning. Median peak plasma concentrations were 5.5∗10-3 mg/ml for oxaliplatin, 89∗10-6 mg/ml for docetaxel (dose 50 mg/m2) and 113∗10-6 mg/ml for docetacel (dose 75 mg/m2). The following morning median plasma concentrations were 32% and 4% of the measured peak concentrations for oxaliplatin and docetaxel, respectively. For both cytostatic agents, no correlation was found between intraperitoneal fluid concentration and peak plasma concentration. High doses oxaliplatin and docetaxel can be given intraperitoneally without causing potentially toxic systemic concentrations.

A real or apparent decrease in glomerular filtration rate in patients using olaparib?

PURPOSE: Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased creatinine levels during olaparib treatment and whether this actually relates to a declined glomerular filtration rate (GFR). METHODS: We retrospectively identified patients using olaparib at the Netherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL) from 2012 until 2020. Patients with at least one plasma or serum sample available at baseline/off treatment and during olaparib treatment were included. Cystatin C levels were measured, creatinine levels were available and renal function was determined by calculating the estimated glomerular filtration rate (eGFR) using the Creatinine Equation (CKD-EPI 2009) and the Cystatin C Equation (CKD-EPI 2012). RESULTS: In total, 66 patients were included. Olaparib treatment was associated with a 14% increase in median creatinine from 72 (inter quartile range (IQR): 22) µmol/L before/off treatment to 82 (IQR: 20) µmol/L during treatment (p < 0.001) and a 13% decrease in median creatinine-derived eGFR from 86 (IQR: 26) mL/min/1.73 m2 before/off treatment to 75 (IQR: 29) mL/min/1.73 m2 during treatment (p < 0.001). Olaparib treatment had no significant effect on median cystatin C levels (p = 0.520) and the median cystatin C-derived eGFR (p = 0.918). CONCLUSIONS: This study demonstrates that olaparib likely causes inhibition of renal transporters leading to a reversible and dose-dependent increase in creatinine and does not affect GFR, since the median cystatin C-derived eGFR was comparable before/off treatment and during treatment of olaparib. Using the creatinine-derived eGFR can give an underestimation of GFR in patients taking olaparib. Therefore, an alternative renal marker such as cystatin C should be used to accurately calculate eGFR in patients taking olaparib.

Correction to: Exposure-survival analyses of pazopanib in renal cell carcinoma and soft tissue sarcoma patients: opportunities for dose optimization.

In the original publication of the article, the second author name has been misspelled.

Pilot Study to Predict Pharmacokinetics of a Therapeutic Gemcitabine Dose From a Microdose.

Microdose studies are exploratory trials to determine early drug pharmacokinetics in humans. In this trial we examined whether the pharmacokinetics of gemcitabine at a therapeutic dose could be predicted from the pharmacokinetics of a microdose. In this prospective, open-label microdosing study, a gemcitabine microdose (100 µg) was given intravenously to participants on day 1, followed by a therapeutic dose (1250 mg/m2 ) on day 2. Gemcitabine and its metabolite 2',2'-difluorodeoxyuracil (dFdU) were quantified in plasma and intracellularly by using liquid chromatography-mass spectrometry). Noncompartmental pharmacokinetic analysis was performed. Ten patients participated in this study. The mean area under the plasma concentration-time curve (AUC0-8 ) of gemcitabine after microdosing was 0.00074 h·mg/L and after therapeutic dosing was 16 h·mg/L. The mean AUC0-8 of dFdU following the microdose and therapeutic dose were 0.022 h·mg/L and 169 h·mg/L, respectively. Exposure to gemcitabine after the therapeutic dose was within 2-fold of the exposure following a microdose, when linearly extrapolated to 1250 mg/m2 . However, the shape of the concentration-time curve was different, as reflected by poor scalability in volume of distribution (939 L versus 222 L). Furthermore, intracellularly phosphorylated gemcitabine and phosphorylated dFdU levels could not be predicted from the microdose. The AUC0-8 of gemcitabine at therapeutic dose was accurately predicted by the pharmacokinetics of a microdose, when linearly extrapolated to 1250 mg/m2 . Volume of distribution, elimination rate constant, and intracellular pharmacokinetics of the therapeutic dose could not be predicted from the microdose, which demonstrates limitations of the microdose approach in this case.

Development and validation of an integrated LC-MS/MS assay for therapeutic drug monitoring of five PARP-inhibitors.

An liquid chromatography-mass spectrometry (LC-MS/MS) assay was developed for the combined analysis of the five poly (ADP-ribose) polymerase (PARP) inhibitors niraparib, olaparib, rucaparib talazoparib and veliparib. A simple and fast sample pre-treatment method was used by protein precipitating of plasma samples with acetonitrile and dilution of the supernatant with formic acid (0.1% v/v in water). This was followed by chromatographic separation on a reversed-phase UPLC BEH C18 column and detection with a triple quadrupole mass spectrometer operating in the positive mode. A simplified validation procedure specifically designed for bioanalytical methods for clinical therapeutic drug monitoring (TDM) purposes, was applied. This included assessment of the calibration model, accuracy and precision, lower limit of quantification (LLOQ), specificity and selectivity, carry-over and stability. The validated range was 30-3000 ng/mL for niraparib, 100-10,000 ng/mL for olaparib, 50-5000 ng/mL for rucaparib, 0.5-50 ng/mL for talazoparib and 50-5000 for veliparib. All results were within the criteria of the US Food and Drug Administration (FDA) guidance and European Medicines Agency (EMA) guidelines on method validation. The assay has been successfully implemented in our laboratory.

[Pharmacotherapy in patients with loss of renal function]. / Farmacotherapie bij nierfunctieverlies.

When dosing renally excreted drugs in patients with kidney disease, it is important to have a reliable estimate of renal function. The estimated glomerular filtration rate (eGFR) is often used in the clinic, although this measure can be inaccurate in certain situations. Choosing the appropriate drug and dosage should therefore not be solely based on the eGFR. In this review, we discuss the physiology behind renal function estimation and drug dosing and propose a step by step approach to dosing renally excreted drugs in patients with kidney disease.