Mina Nikanjam

Nevirapine Exposure with WHO Pediatric Weight Band Dosing: Enhanced Therapeutic Concentrations Predicted Based on Extensive International Pharmacokinetic Experience

ABSTRACT Nevirapine (NVP) is a nonnucleoside reverse transcriptase inhibitor (NNRTI) used worldwide as part of combination antiretroviral therapy in infants and children to treat HIV infection. Dosing based on either weight or body surface area has been approved by the U.S. Food and Drug Administration (FDA) but can be difficult to implement in resource-limited settings. The World Health Organization (WHO) has developed simplified weight band dosing for NVP, but it has not been critically evaluated. NVP pharmacokinetic data were combined from eight pediatric clinical trials (Pediatric AIDS Clinical Trials Group [PACTG] studies 245, 356, 366, 377, 403, 1056, and 1069 and Children with HIV in Africa Pharmacokinetics and Adherence of Simple Antiretroviral Regimens [CHAPAS]) representing subjects from multiple continents and across the pediatric age continuum. A population pharmacokinetic model was developed to characterize developmental changes in NVP disposition, identify potential sources of NVP pharmacokinetic variability, and assess various pediatric dosing strategies and their impact on NVP exposure. Age, CYP2B6 genotype, and ritonavir were independent predictors of oral NVP clearance. The Triomune fixed-dose tablet was an independent predictor of bioavailability compared to the liquid and other tablet formulations. Monte Carlo simulations of the final model were used to assess WHO weight band dosing recommendations. The final pharmacokinetic model indicated that WHO weight band dosing is likely to result in a percentage of children with NVP exposure within the target range similar to that obtained with FDA dosing. Weight band dosing of NVP proposed by the WHO has the potential to provide a simple and effective dosing strategy for resource limited settings.

Dosing de novo combinations of two targeted drugs: Towards a customized precision medicine approach to advanced cancers

Metastatic cancers harbor complex genomic alterations. Thus, monotherapies are often suboptimal. Individualized combinations are needed in order to attenuate resistance. To help inform selection of safe starting doses for novel, two-agent, targeted drug combinations, we identified clinical trials in adult oncology patients who received targeted drug doublets (PubMed, January 1, 2010 through December 31, 2013). The dose percentage was calculated for each drug: (safe dose in combination divided by single agent full dose) X 100. Additive dose percentage represented the sum of the dose percentage for each drug. A total of 144 studies (N = 8568 patients; 95 combinations) were analyzed. In 51% of trials, each of the two drugs could be administered at 100% of their full dose. The lowest safe additive dose percentage was 60% if targets and/or class of drugs overlapped, or in the presence of mTor inhibitors, which sometimes compromised the combination dose. If neither class nor target overlapped and if mTor inhibitors were absent, the lowest safe additive dose percentage was 143%. The current observations contribute to the knowledge base that informs safe starting doses for new combinations of targeted drugs in the context of clinical trials or practice, hence facilitating customized combination therapies.

Developmental Pharmacokinetic Changes of Lamivudine in Infants and Children

Lamivudine is a nucleoside reverse transcriptase inhibitor widely used in infants and children in combination antiretroviral therapy to treat human immunodeficiency virus (HIV) infection. Developmental changes in lamivudine pharmacokinetic disposition were assessed by combining data from 7 studies of lamivudine (Pediatric AIDS Clinical Trials Group 300, 353, 356, 358, 386, 1056, and 1069) representing subjects across the pediatric age continuum. A population pharmacokinetic model was developed to identify factors that influence lamivudine disposition. Age and Thai race were independent predictors of apparent clearance (CL/F), whereas the use of a fixed drug combination formulation (GPO‐VIR) was an independent predictor of bioavailability, with CL/F more than doubling from birth to adolescence. Serum creatinine was not associated with CL/F. Monte Carlo simulations were used to compare the lamivudine exposure achieved with World Health Organization (WHO) weight band and Food and Drug Administration (FDA) label dosing recommendations. WHO dosing yielded higher exposure during the first few months of life, but this difference was less pronounced between 6 months and 14 years of age. Overall, both FDA and WHO dosing provided similar AUC values to those previously reported in HIV‐infected adults. Lamivudine WHO weight band dosing results in therapeutic exposure in infants and children and may improve drug dosing in resource‐limited countries.

ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways

Leukemia cells rely on two nucleotide biosynthetic pathways, de novo and salvage, to produce dNTPs for DNA replication. Here, using metabolomic, proteomic, and phosphoproteomic approaches, we show that inhibition of the replication stress sensing kinase ataxia telangiectasia and Rad3-related protein (ATR) reduces the output of both de novo and salvage pathways by regulating the activity of their respective rate-limiting enzymes, ribonucleotide reductase (RNR) and deoxycytidine kinase (dCK), via distinct molecular mechanisms. Quantification of nucleotide biosynthesis in ATR-inhibited acute lymphoblastic leukemia (ALL) cells reveals substantial remaining de novo and salvage activities, and could not eliminate the disease in vivo. However, targeting these remaining activities with RNR and dCK inhibitors triggers lethal replication stress in vitro and long-term disease-free survival in mice with B-ALL, without detectable toxicity. Thus the functional interplay between alternative nucleotide biosynthetic routes and ATR provides therapeutic opportunities in leukemia and potentially other cancers.Leukemic cells depend on the nucleotide synthesis pathway to proliferate. Here the authors use metabolomics and proteomics to show that inhibition of ATR reduced the activity of these pathways thus providing a valuable therapeutic target in leukemia.

Dosing Three‐Drug Combinations That Include Targeted Anti‐Cancer Agents: Analysis of 37,763 Patients

BACKGROUND Combining targeted and cytotoxic agents has the potential to improve efficacy and attenuate resistance for metastatic cancer. Information regarding safe starting doses for clinical trials of novel three-drug combinations is lacking. MATERIALS AND METHODS Published phase I-III adult oncology clinical trials of three-drug combinations involving a targeted agent were identified by PubMed search (January 1, 2010 to December 31, 2013). A dose percentage was calculated to compare the dose used in combination to the single agent recommended dose: (U.S. Food and Drug Administration-approved/recommended phase II dose/maximum tolerated dose). The additive dose percentage was the sum of the dose percentages for each drug in the combination. RESULTS A total of 37,763 subjects and 243 drug combinations were included. Only 28% of studies could give each of the three agents at 100%. For combinations involving two targeted agents and a cytotoxic agent, the lowest starting additive dose percentage was 133%, which increased to 250% if two antibodies were included. For combinations of one targeted agent and two cytotoxic agents, the lowest additive safe dose percentage was 137%. When both cytotoxic agents were held at 100%, as occurred in 56% of studies (which generally used cytotoxic doublets with known combination safety dosing), the lowest safe dose percentage was 225% (providing that a histone deacetylase inhibitor was not the targeted agent). CONCLUSION These findings serve as a safe starting point for dosing novel three-drug combinations involving a targeted agent in clinical trials and practice. The Oncologist 2017;22:576-584 IMPLICATIONS FOR PRACTICE: Targeted and cytotoxic drug combinations can improve efficacy and overcome resistance. More knowledge of safe starting doses would facilitate use of combinations in clinical trials and practice. Analysis of 37,763 subjects (243 combinations) showed three drugs could be safely administered, but less than 30% of combinations could include all three drugs at full dose. Dose reductions to 45% of the dose of each single agent may be required. Combinations involving two antibodies required fewer dose reductions, and the use of established cytotoxic doublets made initial dose assignment easier.

Dosing targeted and cytotoxic two‐drug combinations: Lessons learned from analysis of 24,326 patients reported 2010 through 2013

Combining agents has the potential to attenuate resistance in metastatic cancer. However, knowledge of appropriate starting doses for novel drug combinations in clinical trials and practice is lacking. Analysis of 372 published studies was used to ascertain safe starting doses for doublets involving a cytotoxic and targeted agent. Phase I–III adult oncology clinical trial publications (January 1, 2010 to December 31, 2013) were identified (PubMed). The dose of drug used in each combination was compared to the single agent recommended dose [FDA‐approved/recommended phase 2 dose (RP2D)/maximum tolerated dose (MTD)]. Dose percentages were calculated as: (safe dose of drug in combination/dose of drug as single agent at FDA/RP2D/MTD) × 100. Additive dose percentages were the sum of the dose percentage for each drug. A total of 24,326 patients (248 drug combinations) were analyzed. In 38% of studies, both drugs could be administered at 100% of their FDA‐approved/RP2D/MTD dose. The lowest safe additive dose percentage was 41% with poly‐ADP ribose polymerase (PARP) or histone deacetylase inhibitors as the targeted agents; 82%, in the absence of these agents; and 97%, with an antibody in the combination. If one drug was administered at 100% of the single agent dose, the lowest safe dose percentage for the second drug was 17% (cytotoxic at 100%) or 36% (targeted at 100%) of the FDA‐approved/RP2D/MTD dose. The current findings can help inform safe starting doses for novel two‐drug combinations (cytotoxic and targeted agents) in the context of clinical trials and practice.

Dosing immunotherapy combinations: Analysis of 3,526 patients for toxicity and response patterns

ABSTRACT Immunotherapy combinations are used to improve outcomes in metastatic cancer, but evidence-based knowledge of appropriate starting doses for novel combinations is lacking. Phase I-III adult combination clinical trials (≥ 1 drug was immunotherapy; anti-PD-1, PD-L1, or CTLA-4) were reviewed (PubMed Jan 1, 2010 to Sep 1, 2016; ASCO 2014–2016, ASH/ESMO 2014–2015 abstracts). The safe dose for each drug used in each combination was divided by the single-agent recommended dose to calculate dose percentage. Additive dose percentage was the sum of each dose percentage. Overall, 84 studies (N = 3,526 patients, 59 combinations) were analyzed. In 50% of studies, all drugs could be administered at full dose; 63%, in the presence of anti-PD-1/PD-L1 and 36% with anti-CTLA-4. The lowest safe starting dose for a doublet combination including a second immunotherapy was 50% of each drug; 60%, for a targeted agent. Most doublet/triplets combining anti-PD-1/PD-L1 with cytotoxics were tolerable at full doses. Response rates (median [interquartile range]) were higher for 3-drug than 2-drug combinations (53% [33–63%] (N = 23 studies) vs. 23% [14–39%]) (N = 60 studies) (p < 0.0001) with similar rates seen for targeted, cytotoxic, biologic, or additional immunotherapy combinations (p = 0.35). In conclusion, anti-PD-1/PD-L1 checkpoint inhibitors can be safely given with a variety of other immunotherapy and targeted agents, albeit at about half dose. Doublet and triplet combinations with cytotoxics could mostly be given at full doses. Anti-CTLA-4 agents compromised dosing more than anti-PD-1/PD-L1 agents. Response rates were significantly higher for 3- versus 2-drug combinations.

Midazolam Single Time Point Concentrations to Estimate Exposure and Cytochrome P450 (CYP) 3A Constitutive Activity Utilizing Limited Sampling Strategy With a Population Pharmacokinetic Approach

Midazolam is the preferred probe to phenotype cytochrome P450 (CYP) 3A activity. This study evaluated a single‐concentration, midazolam limited sampling strategy utilizing a population pharmacokinetic (PK) approach to estimate area under the curve, and thus CYP3A activity. Midazolam concentrations from adults during CYP3A constitutive conditions were obtained from previous studies after single, oral or intravenous administration. Population PK modeling was conducted by nonlinear mixed‐effects modeling. Potential covariates of clearance, volume of distribution, and bioavailability were evaluated. A limited sampling model at 1, 2, 4, or 6 hours was selected and fitted with post hoc estimation with the final population PK model. Preset criterion for the limited sampling model selection was a coefficient of determination ≥0.9. Bias and precision were also evaluated. The studies provided 2122 observations from 152 healthy adults. Midazolam concentrations were adequately described by a two‐compartment model with first order absorption. Age and sex were significant covariates of central volume (V2) and were retained in the final model. An estimate (interindividual variability) of midazolam clearance was 32.5 L/hr (52.9%), covariate of central volume was 67 L (39.1%), and oral bioavailability was 0.33 (45.5%). The final population parameter estimates were within the 95% confidence intervals and were similar to the median bootstrap estimates. Upon comparison to the population PK model, the 4‐hour limited sampling model estimated area under the curve had an acceptable coefficient of determination and acceptable bias and precision limits. A 4‐hour, but not the 1‐, 2‐, and 6‐hour, single concentration accurately estimated midazolam area under the curve during constitutive CYP3A conditions in healthy adults.

Population Pharmacokinetics of Lopinavir/Ritonavir: Changes Across Formulations and Human Development From Infancy Through Adulthood

Lopinavir/ritonavir (LPV/r) is recommended by the World Health Organization as first‐line treatment for HIV‐infected infants and young children. We performed a composite population pharmacokinetic (PK) analysis on LPV plasma concentration data from 6 pediatric and adult studies to determine maturation and formulation effects from infancy to adulthood. Intensive PK data were available for infants, children, adolescents, and adults (297 intensive profiles/1662 LPV concentrations). LPV PK data included 1 adult, 1 combined pediatric‐adult, and 4 pediatric studies (age 6 weeks to 63 years) with 3 formulations (gel‐capsule, liquid, melt‐extrusion tablets). LPV concentrations were modeled using nonlinear mixed effects modeling (NONMEM v. 7.3; GloboMax, Hanover, Maryland) with a one compartment semiphysiologic model. LPV clearance was described by hepatic plasma flow (QHP) times hepatic extraction (EH), with EH estimated from the PK data. Volume was scaled by linear weight (WT/70)1.0. Bioavailability was assessed separately as a function of hepatic extraction and the fraction absorbed from the gastrointestinal tract. The absorption component of bioavailability increased with age and tablet formulation. Monte Carlo simulations of the final model using current World Health Organization weight‐band dosing recommendations demonstrated that participants younger than 6 months of age had a lower area under the drug concentration–time curve (94.8 vs >107.4 μg hr/mL) and minimum observed concentration of drug in blood plasma (5.0 vs > 7.1 μg/mL) values compared to older children and adults. Although World Health Organization dosing recommendations include a larger dosage (mg/m2) in infants to account for higher apparent clearance, they still result in low LPV concentrations in many infants younger than 6 months of age receiving the liquid formulation.

Abstract 4064: Relating tumor drug concentrations to target effect with semi-physiologic PK-PD modeling in drug development: an application using a novel dCK inhibitor

Introduction: While plasma concentrations are commonly studied in preclinical and clinical studies, drug concentrations in tumor and effects on molecular targets may be more appropriate for determining drug dosing and predicting response to therapy. The current study assessed tumor and plasma drug levels of DI87, a novel deoxycytidine kinase (dCK) inhibitor, and determined the relationship to dCK activity using a PET biomarker and imaging. Methods: NSG mice with CEM tumors were treated with DI87 (25 or 50 mg/kg) by oral gavage for a single dose. Tumor and plasma concentrations were assessed over 24 hrs (50 mg/kg dose, 5 times points, N=4 separate mice per time point). Plasma and tumor DI87 concentrations were quantified by LC-MS/MS. dCK activity was determined by PET imaging of a biomarker for dCK activity over 27 hrs ([18F]-clofarabine probe was injected 3 hrs prior to imaging) after a single dose of DI87 (50 mg/kg or 25 mg/kg, 5 time points, 4 mice per time point). Nonlinear mixed effects modeling (NONMEM v. 7.2) was used to build a semi-physiologic pharmacokinetic (PK) model to describe tumor and plasma concentrations (tumor volume fixed to observed median tumor size). The PK model was linked to an inhibitory indirect response pharmacodynamic (PD) model of dCK activity in the tumor using a pooled naive approach to describe the relationship between drug levels in the tumor and dCK inhibition. Results: Peak tumor DI87 concentrations were lower (1.15 ± 0.64 μg/mL vs. 13.5 ± 4.5 μg/mL) and occurred later (9 vs. 3 hr) than peak plasma concentrations. Despite limited tumor sampling, the semi-physiologic model described tumor concentrations well (R 2 =0.71). The PK model had a plasma clearance of 0.52 L/hr/kg with a half-life of 3.7 hr. DI87 exposure in the tumor (AUC) was 17% of that observed in plasma. Maximal and near complete dCK inhibition occurred at 9 hr for both the 50 mg/kg and 25 mg/kg doses with recovery of dCK activity beginning at 27 hr post-dose. The predicted tumor concentration at 12 hr of 0.36 μg/mL was sufficient to maintain maximal dCK inhibition. The initiation of recovery of dCK activity corresponded to the decline in tumor DI87 concentrations, but maintained significant inhibition at 27 hr (25% of baseline). The relationship between dCK activity and DI87 tumor concentrations was well characterized by a sigmoid Emax PD model with a large Hill coefficient. This resulted in a dramatic increase of effect over a small range of concentrations. The EC50 was within the range of tumor concentrations observed in the study (0.21 μg/mL). Conclusions: The use of semi-physiologic PK models that include tumor drug concentrations from limited preclinical data can increase knowledge of the PK-PD for novel therapeutics. This approach enhances understanding of time-dependent effects on molecular drugs targets and can improve selection of rational clinical dosing regimens for phase I clinical trials. Citation Format: Mina Nikanjam, Soumya Poddar, Edmund Capparelli, Thuc Le, Liu Wei, Caius Radu. Relating tumor drug concentrations to target effect with semi-physiologic PK-PD modeling in drug development: an application using a novel dCK inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4064. doi:10.1158/1538-7445.AM2017-4064