Handling of data below the lower limit of quantification (LLOQ), below the limit of quantification (BLOQ) in population pharmacokinetic (PopPK) analyses is important for reducing bias and imprecision in parameter estimation. We aimed to evaluate whether using the concentration data below the LLOQ has superior performance over several established methods. The performance of this approach ("All data") was evaluated and compared to other methods: "Discard," "LLOQ/2," and "LIKE" (likelihood-based). An analytical and residual error model was constructed on the basis of in-house analytical method validations and analyses from literature, with additional included variability to account for model misspecification. Simulation analyses were performed for various levels of BLOQ, several structural PopPK models, and additional influences. Performance was evaluated by relative root mean squared error (RMSE), and run success for the various BLOQ approaches. Performance was also evaluated for a real PopPK data set. For all PopPK models and levels of censoring, RMSE values were lowest using "All data." Performance of the "LIKE" method was better than the "LLOQ/2" or "Discard" method. Differences between all methods were small at the lowest level of BLOQ censoring. "LIKE" method resulted in low successful minimization (<50%) and covariance step success (<30%), although estimates were obtained in most runs (∼90%). For the real PK data set (7.4% BLOQ), similar parameter estimates were obtained using all methods. Incorporation of BLOQ concentrations showed superior performance in terms of bias and precision over established BLOQ methods, and shown to be feasible in a real PopPK analysis.

Quizartinib, a second-generation FLT3 inhibitor, is in clinical development for the treatment of acute myeloid leukemia. We studied its pharmacokinetic interactions with the multidrug efflux transporters ABCB1 and ABCG2 and the multidrug metabolizing enzyme CYP3A, using in vitro transport assays and knockout and transgenic mouse models. Quizartinib was transported by human ABCB1 in vitro, and by mouse (m)Abcb1 and mAbcg2 in vivo. Upon oral administration, the brain accumulation of quizartinib was 6-fold decreased by mAbcb1 and 2-fold by mAbcg2 (together: 12-fold). Unexpectedly, the absence of mAbcb1 resulted in a ∼2-fold lower plasma exposure in Abcb1a/1b-/- and Abcb1a/1b;Abcg2-/- mice, suggesting that loss of mAbcb1 causes compensatory alterations in alternative quizartinib elimination or uptake systems. mAbcb1 and mAbcg2 themselves did not appear to restrict quizartinib oral availability. Oral and intravenous pharmacokinetics of quizartinib were not substantially altered between wild-type, Cyp3a knockout and CYP3A4-humanized mice. All three strains showed relatively high (33-51%) oral bioavailability. If this also applies in humans, this would suggest a limited risk of CYP3A-related inter-individual variation in exposure for this drug. Our results provide a possible rationale for using pharmacological ABCB1/ABCG2 inhibitors together with quizartinib when treating malignant lesions situated in part or in whole behind the blood-brain barrier.

The incidence of neutropenia in metastatic castration-resistant prostate cancer (mCRPC) patients treated with docetaxel has been reported to be lower compared to patients with other solid tumors treated with a similar dose. It is suggested that this is due to increased clearance of docetaxel in mCRPC patients, resulting in decreased exposure. The aims of this study were to (1) determine if exposure in mCRPC patients is lower vs patients with other solid tumors by conducting a meta-analysis, (2) evaluate the incidence of neutropenia in patients with mCRPC vs other solid tumors in a clinical cohort, and (3) discuss potential clinical consequences. A meta-analysis was conducted of studies which reported areas under the plasma concentration-time curves (AUCs) of docetaxel and variability. In addition, grade 3/4 neutropenia was evaluated using logistic regression in a cohort of patients treated with docetaxel. The meta-analysis included 36 cohorts from 26 trials (n = 1150 patients), and showed that patients with mCRPC had a significantly lower mean AUC vs patients with other solid tumors (fold change [95% confidence interval (CI)]: 1.8 [1.5-2.2]), with corresponding AUCs of 1.82 and 3.30 mg∙h/L, respectively. Logistic regression, including 812 patient, demonstrated that patients with mCRPC had a 2.2-fold lower odds of developing grade 3/4 neutropenia compared to patients with other solid tumors (odds ratio [95%CI]: 0.46 [0.31-0.90]). These findings indicate that mCRPC patients have a lower risk of experiencing severe neutropenia, possibly attributable to lower systemic exposure to docetaxel.

The anticancer drug temozolomide is the only drug with proven activity against high-grade gliomas and has therefore become a part of the standard treatment of these tumors. P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2) are transport proteins, which are present at the blood-brain barrier and limit the brain uptake of substrate drugs. We have studied the effect of P-gp and BCRP on the pharmacokinetics and pharmacodynamics of temozolomide, making use of a comprehensive set of in vitro transport experiments and in vivo pharmacokinetic and antitumor efficacy experiments using wild-type, Abcg2-/-, Abcb1a/b-/-, and Abcb1a/b;Abcg2-/- mice. We here show that the combined deletion of Abcb1a/b and Abcg2 increases the brain penetration of temozolomide by 1.5-fold compared to wild-type controls (P < .001) without changing the systemic drug exposure. Moreover, the same increase was achieved when temozolomide was given to wild-type mice in combination with the dual P-gp/BCRP inhibitor elacridar (GF120918). The antitumor efficacy of temozolomide against three different intracranial tumor models was significantly enhanced when Abcb1a/b and Abcg2 were genetically deficient or pharmacologically inhibited in recipient mice. These findings call for further clinical testing of temozolomide in combination with elacridar for the treatment of gliomas, as this offers the perspective of further improving the antitumor efficacy of this already active agent.

Fisogatinib (BLU-554) is a highly selective and potent oral fibroblast growth factor receptor 4 (FGFR4) inhibitor currently in Phase I clinical trials for treatment of hepatocellular carcinoma (HCC). Using (male) genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in fisogatinib pharmacokinetics. In vitro, fisogatinib was modestly transported by hABCB1. Upon oral administration of 10 mg/kg fisogatinib, its brain accumulation was substantially increased in Abcb1a/1b-/- (6.3-fold) and Abcb1a/1b;Abcg2-/- mice (7.2-fold) compared to wild-type mice, but not in single Abcg2-/- mice. The oral plasma pharmacokinetics and liver distribution of fisogatinib were not significantly affected by the absence of Oatp1a/1b drug uptake transporters. We further found that plasma exposure of fisogatinib in Cyp3a-/- mice increased by 1.4-fold, and was subsequently 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. However, the relative tissue distribution of fisogatinib remained unaltered. In summary, in mice, fisogatinib brain accumulation is substantially limited by ABCB1 P-glycoprotein in the blood-brain barrier, and oral availability of fisogatinib is markedly restricted by CYP3A activity. The obtained insights may be useful for optimizing the clinical efficacy and safety of fisogatinib.

Sotorasib (Lumakras™) is the first FDA-approved KRASG12C inhibitor for treatment of patients with non-small cell lung cancer (NSCLC) carrying this mutation. Using genetically modified mouse models, we studied the influence of the efflux transporters ABCB1 and ABCG2, the OATP1a/1b uptake transporters, and the CYP3A drug-metabolizing enzyme complex on the plasma pharmacokinetics and tissue distribution of oral sotorasib. In vitro, sotorasib was a potent substrate for human ABCB1 and a modest substrate for mouse Abcg2, but not for human ABCG2. In vivo, the brain-to-plasma ratio of sotorasib (40 mg/kg) was highly increased in Abcb1a/1b-/- (5.9-fold) and Abcb1a/1b;Abcg2-/- (7.6-fold) compared to wild-type mice, but not in single Abcg2-/- mice. Upon coadministering elacridar, an ABCB1/ABCG2 inhibitor, sotorasib brain accumulation increased 7.5-fold, approaching the levels observed in Abcb1a/1b-deficient mice. No acute CNS toxicity emerged upon boosting of the sotorasib exposure. In Oatp1a/1b-deficient mice, we observed a 2-fold reduction in liver disposition compared to wild-type mice, although these uptake transporters had no noticeable impact on sotorasib plasma exposure. However, plasma exposure was limited by mouse Cyp3a and human CYP3A4, as the AUC0-4 h in Cyp3a-/- mice was increased by 2.5-fold compared to wild-type mice, and subsequently strongly decreased (by 3.9-fold) in Cyp3aXAV mice transgenically overexpressing human CYP3A4 in liver and intestine. Collectively, the oral availability of sotorasib was markedly limited by CYP3A and possibly also by ABCB1 and OATP1a/b, whereas its brain accumulation was strongly restricted by ABCB1. The obtained results may help to further optimize the safety and efficacy of sotorasib in clinical use.

Selpercatinib is a targeted, FDA-approved, oral, small-molecule inhibitor for the treatment of rearranged during transfection (RET) proto-oncogene mutation-positive cancer. Using genetically modified mouse models, we investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, the OATP1A/1B uptake transporters, and the drug-metabolizing CYP3A complex in selpercatinib pharmacokinetics. Selpercatinib was efficiently transported by hABCB1 and mAbcg2, but not hABCG2, and was not a substrate of human OATP1A2, -1B1 or -1B3 in vitro. In vivo, brain and testis penetration were increased by 3.0- and 2.7-fold in Abcb1a/1b-/- mice and by 6.2- and 6.4-fold in Abcb1a/1b;Abcg2-/- mice, respectively. Oatp1a/1b deficiency did not alter selpercatinib pharmacokinetics. The ABCB1/ABCG2 inhibitor elacridar boosted selpercatinib brain penetration in wild-type mice to the levels seen in Abcb1a/1b;Abcg2-/- mice. Cyp3a-/- mice showed a 1.4-fold higher plasma AUC0-4h than wild-type mice, which was then 1.6-fold decreased upon transgenic overexpression of human CYP3A4 in liver and intestine. In summary, ABCG2, and especially ABCB1, limit brain and testis penetration of selpercatinib. Elacridar coadministration could mostly reverse these effects, without causing acute toxicity. CYP3A-mediated metabolism can limit selpercatinib oral exposure and hence its tissue concentrations. These insights may be useful in the further clinical development of selpercatinib.

Over 75 kinase inhibitors (KIs) have been approved for the treatment of various cancers. KIs are orally administrated but mostly lack pediatric age-appropriate dosage forms or instructions for dose manipulation. This is highly problematic for clinical practice in pediatric oncology, as flexible oral formulations are essential to individually set dosages and to adjust it to a child's swallowability. Most KIs are poorly soluble, categorized in Biopharmaceutics Classification System (BCS) class II or IV, and improperly manipulating the KI formulation can alter pharmacokinetics and jeopardize KI drug safety and efficacy. Therefore, the goals of this review were to provide practical recommendations for manipulating the formulation of the 15 most frequently used KIs in pediatric oncology (i.e., bosutinib, cabozantinib, cobimetinib, crizotinib, dabrafenib, dasatinib, entrectinib, imatinib, larotrectinib, nilotinib, ponatinib, ruxolitinib, selumetinib, sunitinib and trametinib) based on available literature studies and fundamental drug characteristics and to establish a decision tool that supports decisions regarding formulation manipulation of solid oral dosages of KIs that have been or will be licensed (for adult and/or pediatric cancers) but are not included in this review.

Olaparib, niraparib, rucaparib, and talazoparib are poly (ADP-ribose) polymerase (PARP) inhibitors approved for the treatment of ovarian, breast, pancreatic, and/or prostate cancer. Poly (ADP-ribose) polymerase inhibitors are potent inhibitors of the PARP enzymes with comparable half-maximal inhibitory concentrations in the nanomolar range. Olaparib and rucaparib are orally dosed twice a day, extensively metabolized by cytochrome P450 enzymes, and inhibitors of several enzymes and drug transporters with a high risk for drug-drug interactions. Niraparib and talazoparib are orally dosed once a day with a lower risk for niraparib and a minimal risk for talazoparib to cause drug-drug interactions. All four PARP inhibitors show moderate-to-high interindividual variability in plasma exposure. Higher exposure is associated with an increase in toxicity, mostly hematological toxicity. For talazoparib, exposure-efficacy relationships have been described, but for olaparib, niraparib, and rucaparib this relationship remains inconclusive. Further studies are required to investigate exposure-response relationships to improve dosing of PARP inhibitors, in which therapeutic drug monitoring could play an important role. In this review, we give an overview of the pharmacokinetic properties of the four PARP inhibitors, including considerations for patients with renal dysfunction or hepatic impairment, the effect of food, and drug-drug interactions. Furthermore, we focus on the pharmacodynamics and summarize the available exposure-efficacy and exposure-toxicity relationships.

Angiosarcoma is an extremely rare and aggressive malignancy. Standard of care of localized tumors includes surgery ± radiation. Despite this multimodal treatment, >50% of the angiosarcoma patients develop local or distant recurrent disease. The role of neoadjuvant systemic therapy is still controversial and we therefore performed a systematic review of the literature to define the role of neoadjuvant systemic therapy based on available evidence. We focused on the effects of neoadjuvant systemic therapy on: 1. The success of surgical resection and 2. the long-term survival. All articles published before October 2019 on Ovid Medline, Ovid Embase, Cochrane library and Scopus were evaluated. Eighteen case reports and six retrospective cohort studies were included. There were no randomized controlled trials. This literature showed a beneficial role of neoadjuvant chemotherapy on downsizing of the tumor resulting in an improvement of the resection margins, especially in patients with cardiac or cutaneous angiosarcoma. However, no definitive conclusions on survival can be drawn based on the available literature lacking any prospective randomized studies in this setting. We advise that neoadjuvant chemotherapy should be considered, since this could lead to less mutilating resections and a higher rate of free resection margins. An international angiosarcoma registry could help to develop guidelines for this rare disease.

Many oral anticancer drugs are metabolized by CYP3A. Clinical drug-drug interaction (DDI) studies often only examine the effect of strong CYP3A inhibitors and inducers. The effect of moderate or weak inhibitors or inducers can be examined using physiologically based pharmacokinetic simulations, but data from these simulations are not always available early after approval of a drug. In this review we provide recommendations for clinical practice on how to deal with DDIs of oral anticancer drugs if only data from strong CYP3A inhibitors or inducers is available. These recommendations were based on reviewed data of oral anticancer drugs primarily metabolized by CYP3A and approved for the treatment of solid tumors from January 1st, 2013 to December 31st, 2015. In addition, three drugs that were registered before the new EMA guideline was issued (i.e., everolimus, imatinib, and sunitinib), were reviewed. DDIs are often complex, but if no data is available from moderate CYP3A inhibitors/inducers, a change in exposure of 50% compared with strong inhibitors/inducers can be assumed. No a priori dose adaptations are indicated for weak inhibitors/inducers, because their interacting effect is small. In case pharmacologically active metabolites are involved, the metabolic pathway, the ratio of the parent to the metabolites, and the potency of the metabolites should be taken into account.

Despite high HIV co-infection prevalence in Ethiopian visceral leishmaniasis (VL) patients, the adequacy of antileishmanial drug exposure in this population and effect of HIV-VL co-morbidity on pharmacokinetics of antileishmanial and antiretroviral (ARV) drugs is still unknown.

Host immune responses are pivotal for the successful treatment of the leishmaniases, a spectrum of infections caused by Leishmania parasites. Previous studies speculated that augmenting cytokines associated with a type 1 T-helper cell (Th1) response is necessary to combat severe forms of leishmaniasis, and it has been hypothesized that the antileishmanial drug miltefosine is capable of immunomodulation and induction of Th1 cytokines. A better understanding of the immunomodulatory effects of miltefosine is central to providing a rationale regarding synergistic mechanisms of activity to combine miltefosine optimally with other conventional and future antileishmanials that are currently under development. Therefore, a systematic literature search was performed to evaluate to what extent and how miltefosine influences the host Th1 response. Miltefosine's effects observed in both a preclinical and a clinical context associated with immunomodulation in the treatment of leishmaniasis are evaluated in this review. A total of 27 studies were included in the analysis. Based on the current evidence, miltefosine is not only capable of inducing direct parasite killing but also of modulating the host immunity. Our findings suggest that miltefosine-induced activation of Th1 cytokines, particularly represented by increased gamma interferon (IFN-γ) and interleukin 12 (IL-12), is essential to prevail over the Leishmania-driven Th2 response. Differences in miltefosine-induced host-mediated effects between in vitro, ex vivo, animal model, and human studies are further discussed. All things considered, an effective treatment with miltefosine is acquired by enhanced functional Th1 cytokine responses and may further be enhanced in combination with immunostimulatory agents.

Azide is a highly toxic chemical agent to human being. Accidental, but also intentional exposure to azide occurs. To be able to confirm azide ingestion, we developed a method to identify and quantify azide in biological matrices. Cyanide was included in the method to evaluate suggested in vivo production of cyanide after azide ingestion. Azide in biological matrices was first derivatized by propionic anhydride to form propionyl azide. Simultaneously, cyanide was converted into hydrogen cyanide. After thermal rearrangement of propionyl azide, ethyl isocyanate was formed, separated together with hydrogen cyanide by gas chromatography (GC) and detected using a nitrogen phosphorous detector (NPD). The method was linear from 1.0-100 µg/mL for both analytes, and azide was stable in human plasma at -20°C for at least 49 days. Azide was measured in the gastric content of two cases of suspected azide ingestion (case 1:1.2 mg/mL, case 2:1.5 mg/mL). Cyanide was only identified in the gastric content of case 1 (approximately 1.4 µg/mL). Furthermore, azide was quantified in plasma (19 µg/mL), serum (24 µg/mL), cell pellet (21 µg/mL) and urine (3.0 µg/mL) of case 2. This method can be used to confirm azide and cyanide exposure, and azide concentrations can be quantified in several biological matrices.

BRCA deficiency predisposes to the development of invasive breast cancer. In BRCA mutation carriers this risk can increase up to 80%. Currently, bilateral prophylactic mastectomy and prophylactic bilateral salpingo-oophorectomy are the only preventive, albeit radical invasive strategies to prevent breast cancer in BRCA mutation carriers. An alternative non-invasive way to prevent BRCA1-associated breast cancer may be local prophylactic treatment via the nipple. Using a non-invasive intraductal (ID) preclinical intervention strategy, we explored the use of combined cisplatin and poly (ADP)-ribose polymerase 1 (PARP1) inhibition to prevent the development of hereditary breast cancer. We show that ID cisplatin and PARP-inhibition can successfully ablate mammary epithelial cells, and this approach attenuated tumor onset in a mouse model of Brca1-associated breast cancer from 153 to 239 days. Long-term carcinogenicity studies in 150 syngeneic wild-type mice demonstrated that tumor incidence was increased in the ID treated mammary glands by 6.3% due to systemic exposure to cisplatin. Although this was only evident in aged mice (median age = 649 days), we conclude that ID cisplatin treatment only presents a safe and feasible local prevention option if systemic exposure to the chemotherapy used can be avoided.

Usual vulvar intraepithelial neoplasia (uVIN) is a premalignancy caused by persistent infection with high-risk types of human papillomavirus (HPV), mainly type 16. Even though different treatment modalities are available (eg, surgical excision, laser evaporation or topical application of imiquimod), these treatments can be mutilating, patients often have recurrences and 2%-8% of patients develop vulvar carcinoma. Therefore, immunotherapeutic strategies targeting the pivotal oncogenic HPV proteins E6 and E7 are being explored to repress carcinogenesis.

Administration of single-agent docetaxel in a weekly schedule may offer similar efficacy, with a more favorable toxicity profile, compared to a three-weekly schedule in patients with metastatic breast cancer.

Introduction MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors. Pharmacokinetics (PK) and pharmacodynamics (PD) of MCLA-128 have been evaluated in preclinical studies in cynomolgus monkeys and mice. The aim of this study was to characterize the PK and PD of MCLA-128 and to predict a safe starting dose and efficacious clinical dose for the First-In-Human study. Methods A PK-PD model was developed based on PK data from cynomolgus monkeys and tumor growth data from a mouse JIMT-1 xenograft model. Allometric scaling was used to scale PK parameters between species. Simulations were performed to predict the safe and efficacious clinical dose, based on AUCs, receptor occupancies and PK-PD model simulations. Results MCLA-128 PK in cynomolgus monkeys was described by a two-compartment model with parallel linear and nonlinear clearance. The xenograft tumor growth model consisted of a tumor compartment with a zero-order growth rate and a first-order dying rate, both affected by MCLA-128. Human doses of 10 to 480 mg q3wk were predicted to show a safety margin of >10-fold compared to the cynomolgus monkey AUC at the no-observed-adverse-effect-level (NOAEL). Doses of ≥360 mg resulted in predicted receptor occupancies above 99% (Cmax and Cave). These doses showed anti-tumor efficacy in the PK-PD model. Conclusions This analysis predicts that a flat dose of 10 to 480 mg q3wk is suitable as starting dose for a First-in-Human study with MCLA-128. Flat doses ≥360 mg q3wk are expected to be efficacious in human, based on receptor occupancies and PK-PD model simulations.

To review the scientific literature on the pharmacokinetics, pharmacodynamics and clinical efficacy and safety of (supervised) oral diacetylmorphine for patients with severe heroin dependence.

Modeling and simulation of pharmacokinetics and pharmacodynamics has previously been shown to be potentially useful in designing Phase I programs of novel anti-cancer agents that show hematological toxicity. In this analysis, a two-stage model-based trial design was evaluated retrospectively using data from the Phase I program with the aurora kinase inhibitor barasertib.