Publications by authors named "Apurvasena Parikh"

13 Publications

  • Page 1 of 1

Phase 1 Study of 2- or 3-Week Dosing of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met, Monotherapy in Patients With Advanced Non-Small Cell Lung Carcinoma.

Clin Cancer Res 2021 Aug 23. Epub 2021 Aug 23.

Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center.

Purpose: Telisotuzumab vedotin (Teliso-V) is an anti-c-Met-directed antibody-drug conjugate. Here, we present safety and efficacy data from a phase 1/1b study of Teliso-V monotherapy evaluated in once-every-2 (Q2W)/3-week (Q3W) schedules in patients with non-small cell lung cancer (NSCLC).

Methods: During dose escalation, patients received Teliso-V monotherapy intravenously Q3W (0.15-3.3 mg/kg) or Q2W (1.6-2.2 mg/kg). The dose-expansion phase enrolled patients with NSCLC and c-Met H-score {greater than or equal to}150 (c-Met+) or amplification/exon 14 skipping mutations. Safety, pharmacokinetics, and efficacy were assessed. Herein, the analysis of patients receiving {greater than or equal to}1.6 mg/kg Q2W or {greater than or equal to}2.4 mg/kg Q3W Teliso-V is reported.

Results: Fifty-two patients with NSCLC were enrolled and received {greater than or equal to}1.6 mg/kg Teliso-V Q2W (n=28) or {greater than or equal to}2.4 mg/kg Teliso-V Q3W (n=24). The most common adverse events were fatigue (54%), peripheral neuropathy (42%), and nausea (38%). No dose-limiting toxicities were observed for Teliso-V Q2W and Q3W up to 2.2 and 2.7 mg/kg, respectively. The recommended phase 2 dose was established at 1.9 mg/kg Q2W and 2.7 mg/kg Q3W on the basis of overall safety and pharmacokinetics. Forty of 52 patients were c-Met+ (33 nonsquamous, six squamous, one mixed histology) and were included in the efficacy-evaluable population. Of those, nine (23%) had objective responses with median duration of response of 8.7 months; median progression-free survival was 5.2 months.

Conclusions: Teliso-V monotherapy was tolerated and showed antitumor activity in c-Met+ NSCLC. On the basis of overall safety, pharmacokinetics, and efficacy outcomes, 1.9 mg/kg Teliso-V Q2W and 2.7 mg/kg Q3W schedules were selected for further clinical development.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0765DOI Listing
August 2021

Safety, pharmacokinetics, and efficacy of budigalimab with rovalpituzumab tesirine in patients with small cell lung cancer.

Cancer Treat Res Commun 2021 25;28:100405. Epub 2021 May 25.

Cancer Care Center, Blacktown Hospital, Sydney, NSW, Australia. Electronic address:

Background: Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti-PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC.

Materials And Methods: This expansion arm of a multicenter, open-label, multi-arm, first-in-human phase 1 clinical trial enrolled adult patients with progressive SCLC. The primary objective was to assess safety and tolerability. Patients received budigalimab 375 mg via intravenous infusion every 3 weeks, and Rova-T was administered as a dose of 0.3 mg/kg intravenously, on day 1 of the first and third 3-week cycle.

Results: As of October 2019, 31 patients with SCLC were enrolled and treated with budigalimab plus Rova-T. The combination was tolerated, with the most common treatment-emergent adverse events (in >30%) being pleural effusion, fatigue, and cough. The overall response rate was 24.1%, with one confirmed complete response and six confirmed partial responses. The overall response rate in patients with high delta-like protein 3 expression was similar (21.1%). The median progression-free survival was 3.48 months.

Conclusion: Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing.

Clinical Trial Registration Number: NCT03000257 Statement on originality of the work The manuscript represents original work and has not been submitted for publication elsewhere nor previously published. Statement of prior presentation Data from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress 2019.
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http://dx.doi.org/10.1016/j.ctarc.2021.100405DOI Listing
May 2021

First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma.

Cancer Immunol Immunother 2021 Jul 3. Epub 2021 Jul 3.

START Madrid-FJD, Hospital Universitario Fundacion Jimenez Diaz, Madrid, Spain.

Background: Budigalimab is a humanized, recombinant immunoglobulin G1 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We present the safety, efficacy, pharmacokinetic (PK), and pharmacodynamic data from patients enrolled in the head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC) expansion cohorts of the phase 1 first-in-human study of budigalimab monotherapy (NCT03000257; registered 15 December 2016).

Patients And Methods: Patients with recurrent/metastatic HNSCC or locally advanced/metastatic NSCLC naive to PD-1/PD-1-ligand inhibitors were enrolled; patients were not selected on the basis of oncogene driver mutations or PD-L1 status. Budigalimab was administered at 250 mg intravenously Q2W or 500 mg intravenously Q4W until disease progression/unacceptable toxicity. The primary endpoints were safety and PK; the secondary endpoint was efficacy. Exploratory endpoints included biomarker assessments.

Results: In total, 81 patients were enrolled (HNSCC: N = 41 [PD-L1 positive: n = 19]; NSCLC: N = 40 [PD-L1 positive: n = 16]); median treatment duration was 72 days (range, 1-617) and 71 days (range, 1-490) for the HNSCC and NSCLC cohorts, respectively. The most frequent grade ≥ 3 treatment-emergent adverse event was anemia (HNSCC: n = 9, 22%; NSCLC: n = 5, 13%). Both dosing regimens had comparable drug exposure and increased interferon gamma-induced chemokines, monokine induced by gamma interferon, and interferon-gamma-inducible protein 10. Objective response rates were 13% (90% CI, 5.1-24.5) in the HNSCC cohort and 19% (90% CI, 9.2-32.6) in the NSCLC cohort. Median progression-free survival was 3.6 months (95% CI, 1.7-4.7) and 1.9 months (95% CI, 1.7-3.7) in the HNSCC and NSCLC cohorts.

Conclusions: The safety, efficacy and biomarker profiles of budigalimab are similar to other PD-1 inhibitors. Development of budigalimab in combination with novel anticancer agents is ongoing.
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http://dx.doi.org/10.1007/s00262-021-02973-wDOI Listing
July 2021

Phase 1 study of telisotuzumab vedotin in Japanese patients with advanced solid tumors.

Cancer Med 2021 04 6;10(7):2350-2358. Epub 2021 Mar 6.

Shizuoka Cancer Center, Shizuoka, Japan.

Telisotuzumab vedotin (formerly ABBV-399) is an antibody-drug conjugate targeting c-Met-overexpressing tumor cells, irrespective of MET gene amplification status. Safety, pharmacokinetics, and preliminary efficacy of telisotuzumab vedotin were evaluated outside of Japan. This phase 1 open-label study evaluated the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of telisotuzumab vedotin in Japanese patients with advanced solid tumors. Telisotuzumab vedotin was administered intravenously at either 2.4 mg/kg (n = 3) or 2.7 mg/kg (n = 6) every 3 weeks, following a 3 + 3 design. Maximum tolerated dose was not reached on the basis of the study design; no dose-limiting toxicity events were observed. The most common treatment-emergent adverse events related to telisotuzumab vedotin were peripheral sensory neuropathy (44%), and nausea, decreased appetite, and decreased white blood cell count (33% each). Most frequent grade ≥3 treatment-emergent adverse events, irrespective of relationship to telisotuzumab vedotin, were decreased neutrophil count and hypoalbuminemia, reported in two patients (22%) each. Systemic exposure of telisotuzumab vedotin at both dose levels was approximately dose proportional. Pharmacokinetic profile in Japanese patients was similar to that previously reported in non-Japanese patients. Two (22%) patients achieved a partial response, six (67%) had stable disease, one (11%) had progressive disease. Overall disease control rate was 89% (eight of nine patients; 95% confidence interval: 51.8%-99.7%]). Median progression-free survival was 7.1 months (95% confidence interval: 1.2-10.4). In conclusion, telisotuzumab vedotin demonstrated a manageable safety profile, with antitumor activity in Japanese patients with advanced solid tumors; the recommended phase 2 dose was confirmed as 2.7 mg/kg every 3 weeks. ClinicalTrials.gov registration number: NCT03311477.
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http://dx.doi.org/10.1002/cam4.3815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982615PMC
April 2021

Assessment of Clinical Drug-Drug Interactions of Elagolix, a Gonadotropin-Releasing Hormone Receptor Antagonist.

J Clin Pharmacol 2020 12 7;60(12):1606-1616. Epub 2020 Jul 7.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA.

Elagolix is an oral gonadotropin-releasing hormone receptor antagonist indicated for the management of endometriosis-associated pain and in combination with estradiol/norethindrone acetate indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women. Elagolix coadministered with estradiol/norethindrone acetate is in late-stage development for the management of heavy menstrual bleeding associated with uterine fibroids. Based on the in vitro profile of elagolix metabolism and disposition, 9 drug-drug interaction (DDI) studies evaluating the victim and perpetrator characteristics of elagolix were conducted in 144 healthy volunteers. As a victim of cytochrome P450 (CYPs) and transporter-mediated DDIs, elagolix area under the curve (AUC) increased by ∼2-fold following coadministration with ketoconazole and by ∼5- and ∼2-fold with single and multiple doses of rifampin, respectively. As a perpetrator, elagolix decreased midazolam AUC (90% confidence interval) by 54% (50%-59%) and increased digoxin AUC by 32% (23%-41%). Elagolix decreased rosuvastatin AUC by 40% (29%-50%). No clinically significant changes in exposure on coadministration with sertraline or fluconazole occurred. A elagolix 150-mg once-daily regimen should be limited to 6 months with strong CYP3A inhibitors and rifampin because of the potential increase in bone mineral density loss, as described in the drug label. A 200-mg twice-daily regimen is recommended for no more than 1 month with strong CYP3A inhibitors and not recommended with rifampin. Elagolix is contraindicated with strong organic anion transporter polypeptide B1 inhibitors (eg, cyclosporine and gemfibrozil). Consider increasing the doses of midazolam and rosuvastatin when coadministered with elagolix, and individualize therapy based on patient response. Clinical monitoring is recommended for P-glycoprotein substrates with a narrow therapeutic window (eg, digoxin). Dose adjustments are not required for sertraline, fluconazole, bupropion (or any CYP2B6 substrate), or elagolix when coadministered.
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http://dx.doi.org/10.1002/jcph.1689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689813PMC
December 2020

Model Informed Dosing Regimen and Phase I Results of the Anti-PD-1 Antibody Budigalimab (ABBV-181).

Clin Transl Sci 2021 01 26;14(1):277-287. Epub 2020 Dec 26.

Next Oncology, San Antonio, Texas, USA.

Budigalimab is a humanized, recombinant, Fc mutated IgG1 monoclonal antibody targeting programmed cell death 1 (PD-1) receptor, currently in phase I clinical trials. The safety, efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), and budigalimab dose selection from monotherapy dose escalation and multihistology expansion cohorts were evaluated in patients with previously treated advanced solid tumors who received budigalimab at 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) in dose escalation, including Japanese patients that received 3 and 10 mg/kg Q2W. PK modeling and PK/PD assessments informed the dosing regimen in expansion phase using data from body-weight-based dosing in the escalation phase, based on which patients in the multihistology expansion cohort received flat doses of 250 mg Q2W or 500 mg every four weeks (Q4W). Immune-related adverse events (AEs) were reported in 11 of 59 patients (18.6%), of which 1 of 59 (1.7%) was considered grade ≥ 3 and the safety profile of budigalimab was consistent with other PD-1 targeting agents. No treatment-related grade 5 AEs were reported. Four responses per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were reported in the dose escalation cohort and none in the multihistology expansion cohort. PK of budigalimab was approximately dose proportional and sustained > 99% peripheral PD-1 receptor saturation was observed by 2 hours postdosing, across doses. PK/PD and safety profiles were comparable between Japanese and Western patients, and exposure-safety analyses did not indicate any trends. Observed PK and PD-1 receptor saturation were consistent with model predictions for flat doses and less frequent regimens, validating the early application of PK modeling and PK/PD assessments to inform the recommended dose and regimen, following dose escalation.
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http://dx.doi.org/10.1111/cts.12855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877859PMC
January 2021

First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody-Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors.

J Clin Oncol 2018 11 4;36(33):3298-3306. Epub 2018 Oct 4.

John H. Strickler, Duke University Medical Center, Durham, NC; Colin D. Weekes, University of Colorado, Aurora, CO; John Nemunaitis, Mary Crowley Cancer Research Center, Dallas, TX; Ramesh K. Ramanathan, Virginia Piper Cancer Center at Honor Health/Translational Genomics Research Institute, Scottsdale, AZ; Rebecca S. Heist, Massachusetts General Hospital Cancer Center, Boston, MA; Daniel Morgensztern, Washington University School of Medicine, St. Louis, MO; Eric Angevin, Gustave Roussy, Villejuif, France; Todd M. Bauer, Sarah Cannon Research Institute; Todd M. Bauer, Tennessee Oncology, Nashville, TN; Huibin Yue, Daniel Afar, and Louie Naumovski, AbbVie Inc.; Apurvasena Parikh, Clinical Pharmacology and Pharmacometrics, AbbVie Inc., Redwood City; Karen Kelly, University of California Davis Comprehensive Cancer Center, Sacramento, CA; and Monica Motwani, Edward B. Reilly, AbbVie Inc., North Chicago, IL.

Purpose: This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody-drug conjugate of the anti-c-Met monoclonal antibody ABT-700 and monomethyl auristatin E.

Materials And Methods: For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non-small-cell lung cancer (NSCLC) with c-Met-overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score ≥ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined.

Results: Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V-related grade ≥ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met-positive NSCLC. Of 16 patients with c-Met-positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response.

Conclusion: Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met-positive NSCLC.
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http://dx.doi.org/10.1200/JCO.2018.78.7697DOI Listing
November 2018

Are Clinical Therapeutic Protein-Drug Interaction Studies Needed When Disease Modification Is Driving the Potential Interaction?

J Clin Pharmacol 2018 10 21;58(10):1371-1372. Epub 2018 Aug 21.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.

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http://dx.doi.org/10.1002/jcph.1290DOI Listing
October 2018

Industry Perspective on Standardizing Food-Effect Studies for New Drug Development.

Clin Pharmacokinet 2018 08;57(8):901-909

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., 1 North Waukegan Road, North Chicago, IL, 60064-1802, USA.

Investigating the effect of food on bioavailability during the development of an oral drug product is of prime importance because it has major implications on the study design of the clinical trials and dosing and administration recommendations. For modified-release formulations that exhibit dose dumping when administered with food, this may result in clinical concerns around safety and efficacy. In this article, we provide an overview of the various considerations in our opinion that impact the design and conduct of food-effect studies. We summarize the various recommendations from the different regulatory agencies and provide specific suggestions on study conduct in terms of statistical design, timing of studies, subject selection, and type and caloric content of the meal. We also discuss the role of modeling and simulation. Finally, we present an interpretation of the results of food-effect studies in addition to dosing and labeling recommendations in relation to regulatory guidance documents.
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http://dx.doi.org/10.1007/s40262-018-0630-0DOI Listing
August 2018

Exposure-response evaluations of venetoclax efficacy and safety in patients with non-Hodgkin lymphoma.

Leuk Lymphoma 2018 04 10;59(4):871-879. Epub 2017 Aug 10.

a Clinical Pharmacology and Pharmacometrics , Abbvie Inc , North Chicago , IL , USA.

Exposure-response analyses were performed for a venetoclax monotherapy study in 106 patients with varying subtypes of non-Hodgkin lymphoma (NHL) (NCT01328626). Logistic regression, time-to-event, and progression-free survival (PFS) analyses were used to evaluate the relationship between venetoclax exposure, NHL subtype and response, PFS, or occurrence of serious adverse events. Trends for small increases in the probability of response with increasing venetoclax exposures were identified, and became more evident when assessed by NHL subtype. Trends in exposure-PFS were shown for the mantle cell lymphoma (MCL) subtype, but not other subtypes. There was no increase in the probability of experiencing a serious adverse event with increasing exposure. Overall, the results indicate that venetoclax doses of 800-1200 mg as a single agent may be appropriate to maximize efficacy in MCL, follicular lymphoma, and diffuse large B-cell lymphoma subtypes with no expected negative impact on safety.
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http://dx.doi.org/10.1080/10428194.2017.1361024DOI Listing
April 2018

Effect of co-medications on paritaprevir, ritonavir, ombitasvir, dasabuvir and ribavirin pharmacokinetics: analysis of data from seven Phase II/III trials.

Antivir Ther 2016 1;21(8):707-714. Epub 2016 Sep 1.

Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA.

Background: The three drug direct-acting antiviral regimen (3D regimen) of ombitasvir, paritaprevir/ritonavir and dasabuvir, with and without ribavirin, was evaluated in one Phase II trial and six Phase III trials in over 2,300 HCV genotype-1-infected patients. Patients continued taking their protocol-permitted co-medications while receiving the 3D ± ribavirin regimen. The effects of the co-medications on exposures of the 3D regimen and ribavirin were examined.

Methods: Population pharmacokinetic model-predicted steady-state area under the curve (AUC) values were evaluated in the presence/absence of the co-medications. Interactions resulting in a greater than 50% reduction or 100% increase in an AUC value were examined as covariates for an effect on apparent clearance (CL/F).

Results: More than 1,200 co-medications belonging to 15 drug classes and/or 19 enzyme and transporter inhibitor and/or inducer categories were used concomitantly with the 3D regimen in the trials. Approximately 1,500 patients (65%) in Phase III trials received two or more co-medications from multiple drug classes or categories. No co-medication class/category decreased or increased ombitasvir, dasabuvir, ritonavir or ribavirin AUC by more than half or twofold, respectively. Opioids, antipsychotics, anti-epileptics, antidiabetics and non-ethinyl estradiol-containing hormone replacement therapies appeared to have an effect (AUC ratio ≤0.5 or ≥2.0) on paritaprevir exposures. However, when these classes were included in the paritaprevir population pharmacokinetic model, only opioids and antidiabetics had a statistically significant effect on CL/F, but with no clinically meaningful increase in exposures (≤55%).

Conclusions: No dose adjustment is necessary for the 3D ± ribavirin regimen when used with the co-medications included in this analysis as there were no clinically meaningful effects on exposures of the DAAs.
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http://dx.doi.org/10.3851/IMP3079DOI Listing
February 2018

Pharmacokinetics of Tacrolimus and Cyclosporine in Liver Transplant Recipients Receiving 3 Direct-Acting Antivirals as Treatment for Hepatitis C Infection.

Ther Drug Monit 2016 10;38(5):640-5

Departments of *Clinical Pharmacokinetics and Pharmacodynamics; †Infectious Disease Development; and ‡Biometrics, AbbVie Inc, North Chicago, Illinois. E. P. Coakley is now with Alnylam Pharmaceuticals, Cambridge, Massachusetts.

Background: Interactions between tacrolimus and cyclosporine (CSA) and the 3 direct-acting antiviral regimen (3D) of ombitasvir, paritaprevir/ritonavir, and dasabuvir necessitate a priori dose adjustments for the immunosuppressants to achieve desired levels. Modeling and simulations based on data in healthy subjects predicted that tacrolimus 0.5 mg every 7 days or 0.2 mg every 3 days, and CSA at one-fifth the total daily dose administered once daily, would achieve desired trough concentrations (Ctrough) during 3D treatment. The success of these dosing recommendations was evaluated by analyzing pharmacokinetic data from liver transplant recipients in the CORAL-I study.

Methods: A population pharmacokinetic model was developed using tacrolimus dosing and Ctrough data before and during 3D treatment (n = 29). The model was used to simulate various tacrolimus dosing regimens and predict tacrolimus concentration-time profiles during 3D treatment. CSA Ctrough data before and during 3D treatment (n = 5) were also summarized.

Results: A one-compartment model with first-order absorption adequately described tacrolimus pharmacokinetic profiles during the first 4 weeks of 3D treatment. Estimated tacrolimus Ctrough values (median; interquartile range) before and during 3D treatment were comparable (5.7 ng/mL; 4.9-6.5 ng/mL versus 5.2 ng/mL; 4.2-6.3 ng/mL, respectively). Based on simulations, in a patient with a starting Ctrough of 6 ng/mL, 0.5 mg tacrolimus every 7 or 14 days or 0.2 mg tacrolimus every 3 days will result in Ctrough levels of 6-9 ng/mL, 4-6 ng/mL, and 6-10 ng/mL, respectively, during 3D treatment. For CSA, Ctrough values (median; interquartile range) before and during 3D treatment were comparable (126 ng/mL; 94-140 ng/mL versus 104 ng/mL; 82-140 ng/mL).

Conclusions: Observed data for tacrolimus and CSA in liver transplant recipients confirm that the recommended dosing strategies are valid and therapeutic levels of immunosuppression can be maintained during 3D treatment.
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http://dx.doi.org/10.1097/FTD.0000000000000315DOI Listing
October 2016

Crystallographic analysis of human hemoglobin elucidates the structural basis of the potent and dual antisickling activity of pyridyl derivatives of vanillin.

Acta Crystallogr D Biol Crystallogr 2011 Nov 19;67(Pt 11):920-8. Epub 2011 Oct 19.

Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

Vanillin has previously been studied clinically as an antisickling agent to treat sickle-cell disease. In vitro investigations with pyridyl derivatives of vanillin, including INN-312 and INN-298, showed as much as a 90-fold increase in antisickling activity compared with vanillin. The compounds preferentially bind to and modify sickle hemoglobin (Hb S) to increase the affinity of Hb for oxygen. INN-312 also led to a considerable increase in the solubility of deoxygenated Hb S under completely deoxygenated conditions. Crystallographic studies of normal human Hb with INN-312 and INN-298 showed that the compounds form Schiff-base adducts with the N-terminus of the α-subunits to constrain the liganded (or relaxed-state) Hb conformation relative to the unliganded (or tense-state) Hb conformation. Interestingly, while INN-298 binds and directs its meta-positioned pyridine-methoxy moiety (relative to the aldehyde moiety) further down the central water cavity of the protein, that of INN-312, which is ortho to the aldehyde, extends towards the surface of the protein. These studies suggest that these compounds may act to prevent sickling of SS cells by increasing the fraction of the soluble high-affinity Hb S and/or by stereospecific inhibition of deoxygenated Hb S polymerization.
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http://dx.doi.org/10.1107/S0907444911036353DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3211971PMC
November 2011
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