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Article ; Online: Correction to: Evaluation of the absolute oral bioavailability of the anaplastic lymphoma kinase/c-ROS oncogene 1 kinase inhibitor lorlatinib in healthy participants.

Hibma, Jennifer E / O'Gorman, Melissa / Nepal, Sunil / Pawlak, Sylvester / Ginman, Katherine / Pithavala, Yazdi K

2022 Volume 89, Issue 6, Page(s) 839

Language	English
Publishing date	2022-03-18
Publishing country	Germany
Document type	Published Erratum
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-022-04421-7
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Article ; Online: Evaluation of the absolute oral bioavailability of the anaplastic lymphoma kinase/c-ROS oncogene 1 kinase inhibitor lorlatinib in healthy participants.

Hibma, Jennifer E / O'Gorman, Melissa / Nepal, Sunil / Pawlak, Sylvester / Ginman, Katherine / Pithavala, Yazdi K

Cancer chemotherapy and pharmacology

2021 Volume 89, Issue 1, Page(s) 71–81

Abstract: Purpose: Lorlatinib is a third-generation tyrosine kinase inhibitor currently approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. This open-label, phase 1, randomized two-sequence, two-treatment, ...

Abstract	Purpose: Lorlatinib is a third-generation tyrosine kinase inhibitor currently approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. This open-label, phase 1, randomized two-sequence, two-treatment, two-period, crossover study investigated the absolute oral bioavailability of lorlatinib in healthy participants. Methods: Eligible participants were randomized to receive two treatments in one of two sequences: lorlatinib 100 mg single oral dose followed by lorlatinib 50 mg intravenous (IV) dose, or lorlatinib IV dose followed by lorlatinib oral dose, each with at least a 10-day washout between successive lorlatinib doses. Blood samples for pharmacokinetics were collected for up to 144 hours (h) after dosing. Validated liquid chromatographic-tandem mass spectrometry was used to determine plasma concentrations of lorlatinib and its benzoic acid metabolite PF-06895751. Results: In total, 11 participants were enrolled (mean age 37.6 years, all male). The adjusted geometric mean (90% confidence interval) for the absolute oral bioavailability was 80.78% (75.73-86.16%). Using non-compartmental analysis, the estimated arithmetic mean elimination plasma half-life of lorlatinib was 25.5 and 27.0 h after the oral and IV doses, respectively. No deaths, serious adverse events (AEs), or severe AEs were reported, and most treatment-emergent AEs were mild in severity, with two events of transaminase increase of moderate severity. All treatment-emergent AEs were resolved by the end of the study. Conclusion: Both oral and IV lorlatinib were well-tolerated in healthy participants and oral lorlatinib is highly bioavailable after oral administration.
MeSH term(s)	Administration, Oral ; Adult ; Aminopyridines/administration & dosage ; Aminopyridines/adverse effects ; Aminopyridines/blood ; Aminopyridines/pharmacokinetics ; Anaplastic Lymphoma Kinase/antagonists & inhibitors ; Biological Availability ; Healthy Volunteers ; Humans ; Injections, Intravenous ; Lactams/administration & dosage ; Lactams/adverse effects ; Lactams/blood ; Lactams/pharmacokinetics ; Male ; Middle Aged ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/adverse effects ; Protein Kinase Inhibitors/blood ; Protein Kinase Inhibitors/pharmacokinetics ; Pyrazoles/administration & dosage ; Pyrazoles/adverse effects ; Pyrazoles/blood ; Pyrazoles/pharmacokinetics
Chemical Substances	Aminopyridines ; Lactams ; Protein Kinase Inhibitors ; Pyrazoles ; ALK protein, human (EC 2.7.10.1) ; Anaplastic Lymphoma Kinase (EC 2.7.10.1) ; lorlatinib (OSP71S83EU)
Language	English
Publishing date	2021-10-26
Publishing country	Germany
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	6820-2
ISSN	1432-0843 ; 0344-5704 ; 0943-9404
ISSN (online)	1432-0843
ISSN	0344-5704 ; 0943-9404
DOI	10.1007/s00280-021-04368-1
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Article ; Online: Effects of itraconazole and carbamazepine on the pharmacokinetics of nirmatrelvir/ritonavir in healthy adults.

Cox, Donna S / Van Eyck, Lien / Pawlak, Sylvester / Beckerman, Bruce / Linn, Carlos / Ginman, Katherine / Thay Cha, Youliny / LaBadie, Robert R / Shi, Haihong / Damle, Bharat

British journal of clinical pharmacology

2023 Volume 89, Issue 9, Page(s) 2867–2876

Abstract: Aims: The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir.: Methods: Pharmacokinetics ... ...

Abstract	Aims: The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir. Methods: Pharmacokinetics were measured in two phase 1, open-label, fixed-sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed. Results: Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUC Conclusions: Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe.
MeSH term(s)	Adult ; Humans ; Itraconazole/adverse effects ; Ritonavir/adverse effects ; Drug Interactions ; Cytochrome P-450 CYP3A Inhibitors/pharmacology ; Cytochrome P-450 CYP3A Inducers ; Carbamazepine/adverse effects ; Area Under Curve ; Healthy Volunteers ; Cytochrome P-450 CYP3A
Chemical Substances	Itraconazole (304NUG5GF4) ; Ritonavir (O3J8G9O825) ; Cytochrome P-450 CYP3A Inhibitors ; Cytochrome P-450 CYP3A Inducers ; Carbamazepine (33CM23913M) ; Cytochrome P-450 CYP3A (EC 1.14.14.1)
Language	English
Publishing date	2023-05-31
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.15788
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Article ; Online: Safety, Tolerability, and Pharmacokinetics of Intravenous Doses of PF-07304814, a Phosphate Prodrug Protease Inhibitor for the Treatment of SARS-CoV-2, in Healthy Adult Participants.

Zhu, Tong / Pawlak, Sylvester / Toussi, Sima S / Hackman, Frances / Thompson, Kimberly / Song, Wei / Salageanu, Joanne / Winter, Erica / Shi, Haihong / Winton, Jennifer / Binks, Michael

Clinical pharmacology in drug development

2022 Volume 11, Issue 12, Page(s) 1382–1393

Abstract: Studies on targeted antivirals for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing pandemic, are limited. PF-07304814 (lufotrelvir) is the phosphate prodrug of PF-00835231, a protease inhibitor ... ...

Abstract	Studies on targeted antivirals for treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of the ongoing pandemic, are limited. PF-07304814 (lufotrelvir) is the phosphate prodrug of PF-00835231, a protease inhibitor targeting the 3C-like protease of SARS-CoV-2. This phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of single ascending intravenous doses of lufotrelvir (continuous 24-hour infusion of 50, 150, 500, or 700 mg) versus placebo in healthy volunteers (2 interleaving cohorts: 1, n = 8; 2, n = 7). Each dosing period was separated by a washout interval (≥5 days). Treatment-emergent adverse events, PK, and biomarker concentrations were estimated from plasma/urine samples. Lufotrelvir was administered to 15 volunteers (mean [SD] age 39.7 [11.8] years). No serious adverse events, discontinuations, or deaths were reported. Mean maximum observed concentration of PF-00835231 (active moiety; 97.0 ng/mL to 1288 ng/mL) were observed between median time to maximum concentration of 14 to 16 hours after the start of the lufotrelvir infusion. Near-maximum plasma concentrations of PF-00835231 were observed ≈6 hours after infusion start and sustained until infusion end. PF-00835231 plasma concentrations declined rapidly after infusion end (mean terminal half-life: 500 mg, 2.0 hours; 700 mg, 1.7 hours). Approximately 9%-11% of the dose was recovered in urine as PF-00835231 across doses. A continuous, single-dose, 24-hour infusion of lufotrelvir (50-700 mg) was rapidly converted to PF-00835231 (active moiety), with dose-proportional PK exposures and no significant safety concerns. A daily, 24-hour continuous infusion of 270 to 350 mg is expected to maintain PF-00835231 concentration at steady state/above effective antiviral concentrations. Further studies exploring lufotrelvir efficacy in patients with coronavirus disease 2019 are ongoing.
MeSH term(s)	Adult ; Humans ; Antiviral Agents/adverse effects ; COVID-19 Drug Treatment ; Healthy Volunteers ; Indoles ; Organophosphates ; Phosphates ; Prodrugs/adverse effects ; Protease Inhibitors/adverse effects ; Pyrrolidinones ; SARS-CoV-2
Chemical Substances	Antiviral Agents ; Indoles ; Organophosphates ; Phosphates ; Prodrugs ; Protease Inhibitors ; Pyrrolidinones
Language	English
Publishing date	2022-10-26
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.1174
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Article ; Online: Correction to: The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants.

Chen, Joseph / Xu, Huiping / Pawlak, Sylvester / James, Leonard P / Peltz, Gerson / Lee, Kimberly / Ginman, Katherine / Bergeron, Michelle / Pithavala, Yazdi K

Advances in therapy

2020 Volume 37, Issue 11, Page(s) 4754

Abstract: In the original article, the reference 4 has been published and cited incorrectly. ...

Abstract	In the original article, the reference 4 has been published and cited incorrectly.
Language	English
Publishing date	2020-09-10
Publishing country	United States
Document type	Published Erratum
ZDB-ID	632651-1
ISSN	1865-8652 ; 0741-238X
ISSN (online)	1865-8652
ISSN	0741-238X
DOI	10.1007/s12325-020-01480-1
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Article ; Online: The Effect of Rifampin on the Pharmacokinetics and Safety of Lorlatinib: Results of a Phase One, Open-Label, Crossover Study in Healthy Participants.

Chen, Joseph / Xu, Huiping / Pawlak, Sylvester / James, Leonard P / Peltz, Gerson / Lee, Kimberly / Ginman, Katherine / Bergeron, Michelle / Pithavala, Yazdi K

Advances in therapy

2019 Volume 37, Issue 2, Page(s) 745–758

Abstract: Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of ...

Abstract	Introduction: Lorlatinib is a third-generation tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer; cytochrome P450 (CYP) 3A plays an important role in the metabolism of lorlatinib. Methods: This phase 1, open-label, two-period, crossover study estimated the effect of oral rifampin (a strong CYP3A inducer) on the pharmacokinetics and safety of oral lorlatinib (NCT02804399). Healthy participants received single-dose lorlatinib 100 mg in period 1 followed by rifampin 600 mg/day (days 1-12) and single-dose lorlatinib 100 mg (day 8) in period 2. Blood samples were collected for 120 h after each dose of lorlatinib. Results: When a single dose of lorlatinib was administered during daily dosing with rifampin (period 2), the area under the plasma concentration-time profile extrapolated to infinity (AUC Conclusions: The addition of a single dose of lorlatinib to daily dosing with rifampin significantly reduced lorlatinib plasma exposure relative to a single dose of lorlatinib administered alone and was associated with severe but self-limiting transaminase elevations in all healthy participants. These observations support the contraindication in the product label against concomitant use of lorlatinib with all strong CYP3A inducers. Trial registration: ClinicalTrials.gov identifier, NCT02804399.
MeSH term(s)	Adult ; Antineoplastic Agents/therapeutic use ; Area Under Curve ; Carcinoma, Non-Small-Cell Lung/drug therapy ; Cross-Over Studies ; Drug Interactions ; Female ; Healthy Volunteers ; Humans ; Lactams, Macrocyclic/pharmacokinetics ; Lactams, Macrocyclic/therapeutic use ; Lung Neoplasms/drug therapy ; Male ; Middle Aged ; Rifampin/pharmacokinetics ; Rifampin/therapeutic use ; Young Adult
Chemical Substances	Antineoplastic Agents ; Lactams, Macrocyclic ; lorlatinib (OSP71S83EU) ; Rifampin (VJT6J7R4TR)
Language	English
Publishing date	2019-12-20
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632651-1
ISSN	1865-8652 ; 0741-238X
ISSN (online)	1865-8652
ISSN	0741-238X
DOI	10.1007/s12325-019-01198-9
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Article ; Online: Innovative Randomized Phase I Study and Dosing Regimen Selection to Accelerate and Inform Pivotal COVID-19 Trial of Nirmatrelvir.

Singh, Ravi Shankar P / Toussi, Sima S / Hackman, Frances / Chan, Phylinda L / Rao, Rohit / Allen, Richard / Van Eyck, Lien / Pawlak, Sylvester / Kadar, Eugene P / Clark, Frances / Shi, Haihong / Anderson, Annaliesa S / Binks, Michael / Menon, Sandeep / Nucci, Gianluca / Bergman, Arthur

Clinical pharmacology and therapeutics

2022 Volume 112, Issue 1, Page(s) 101–111

Abstract: Coronavirus disease 2019 (COVID-19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, severe acute respiratory syndrome- ... ...

Abstract	Coronavirus disease 2019 (COVID-19) is a continued leading cause of hospitalization and death. Safe, efficacious COVID-19 antivirals are needed urgently. Nirmatrelvir (PF-07321332), the first orally bioavailable, severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) M
MeSH term(s)	Antiviral Agents/pharmacokinetics ; Humans ; Lactams ; Leucine ; Nitriles ; Proline ; Ritonavir ; SARS-CoV-2 ; COVID-19 Drug Treatment
Chemical Substances	Antiviral Agents ; Lactams ; Nitriles ; nirmatrelvir (7R9A5P7H32) ; Proline (9DLQ4CIU6V) ; Leucine (GMW67QNF9C) ; Ritonavir (O3J8G9O825)
Language	English
Publishing date	2022-05-04
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	123793-7
ISSN	1532-6535 ; 0009-9236
ISSN (online)	1532-6535
ISSN	0009-9236
DOI	10.1002/cpt.2603
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Article ; Online: First-in-human, randomized dose-escalation study of the safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of PF-06480605 in healthy subjects.

Banfield, Christopher / Rudin, Dan / Bhattacharya, Indranil / Goteti, Kosalaram / Li, Gang / Hassan-Zahraee, Mina / Brown, Lisa S / Hung, Kenneth E / Pawlak, Sylvester / Lepsy, Christopher

British journal of clinical pharmacology

2020 Volume 86, Issue 4, Page(s) 812–824

Abstract: Aims: Human genetic, tissue expression, proteomics, transcriptomics and nonclinical studies implicate tumour necrosis factor α-like ligand 1A (TL1A) as a novel target in inflammatory bowel disease (IBD). PF-06480605, a fully human immunoglobulin G1 ... ...

Abstract	Aims: Human genetic, tissue expression, proteomics, transcriptomics and nonclinical studies implicate tumour necrosis factor α-like ligand 1A (TL1A) as a novel target in inflammatory bowel disease (IBD). PF-06480605, a fully human immunoglobulin G1 monoclonal antibody, targets TL1A. This first-in-human, Phase 1, dose-escalation study assessed safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of intravenous (IV) and subcutaneous (SC) PF-06480605 in healthy subjects (NCT01989143). Methods: Ninety-two subjects were randomized to single ascending doses (SAD), PF-06480605 1 mg, 3 mg, 10 mg, 30 mg, 100 mg, 300 mg, 600 mg or 800 mg IV, or multiple ascending doses (MAD), PF-06480605 3 × 500 mg IV, or 3 × 30 mg, 3 × 100 mg, or 3 × 300 mg SC every 2 weeks for three doses, or placebo. Safety, tolerability, pharmacokinetics, immunogenicity profiles and total TL1A, anti-drug antibody (ADA) and neutralizing antibody (NAb) levels were assessed at pre-determined times. Results: PF-06480605 SAD up to 800 mg IV and MAD up to 300 mg ×3 SC and 500 mg ×3 IV were well tolerated. Overall, there were 45 and 44 treatment-emergent adverse events in SAD and MAD cohorts, respectively, and no deaths or serious adverse events. PF-06480605 exposure generally increased dose-dependently. ADA and NAb levels did not impact safety, pharmacokinetics, or pharmacodynamics at higher doses. Target engagement was demonstrated through dose-dependent differences in serum total soluble TL1A concentrations for PF-06480605 vs placebo cohorts. Conclusions: PF-06480605 was generally well tolerated, and binding of soluble TL1A was maintained throughout the dose interval, supporting further study of PF-06480605 in patients with IBD and other inflammatory conditions.
MeSH term(s)	Administration, Intravenous ; Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antineoplastic Agents, Immunological ; Dose-Response Relationship, Drug ; Double-Blind Method ; Healthy Volunteers ; Humans
Chemical Substances	Antibodies, Monoclonal ; Antibodies, Neutralizing ; Antineoplastic Agents, Immunological
Language	English
Publishing date	2020-01-28
Publishing country	England
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	188974-6
ISSN	1365-2125 ; 0306-5251 ; 0264-3774
ISSN (online)	1365-2125
ISSN	0306-5251 ; 0264-3774
DOI	10.1111/bcp.14187
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Article ; Online: Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Domagrozumab (PF-06252616), an Antimyostatin Monoclonal Antibody, in Healthy Subjects.

Bhattacharya, Indranil / Pawlak, Sylvester / Marraffino, Shannon / Christensen, Jared / Sherlock, Sarah P / Alvey, Christine / Morris, Carl / Arkin, Steven / Binks, Michael

Clinical pharmacology in drug development

2017 Volume 7, Issue 5, Page(s) 484–497

Abstract: Safety, tolerability, anabolic effects, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses of domagrozumab, an antimyostatin monoclonal antibody, were assessed following intravenous (IV) and subcutaneous (SC) administration in ... ...

Abstract	Safety, tolerability, anabolic effects, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses of domagrozumab, an antimyostatin monoclonal antibody, were assessed following intravenous (IV) and subcutaneous (SC) administration in healthy subjects. A range of single ascending dose levels between 1 and 40 mg/kg IV and multiple doses (3 doses) of 10 mg/kg IV were tested (n = 8 per cohort). Additionally, a 3 mg/kg SC (n = 8) cohort also received domagrozumab. Magnetic resonance imaging and whole-body dual-energy x-ray absorptiometry imaging were conducted to investigate the anabolic effects of domagrozumab. Domagrozumab was well tolerated with no severe and 1 non-treatment-related serious adverse event. The most commonly reported adverse events were headache (21 subjects) and fatigue, upper respiratory tract infections, and muscle spasms (10 subjects each). Domagrozumab demonstrated typical IgG1 pharmacokinetics, with slow SC absorption and slow clearance, low volume of distribution, and a long half-life. Target engagement was observed with an increase in extent of myostatin modulation, plateauing at the 20 mg/kg IV dose. Downstream pharmacology following myostatin binding by domagrozumab was only observed in the 10 mg/kg single IV cohort (increase in whole-body lean mass of 5.38% using dual-energy x-ray absorptiometry) and the 10 mg/kg repeat-dose cohort (muscle volume increase of 4.49% using magnetic resonance imaging).
MeSH term(s)	Absorptiometry, Photon ; Administration, Intravenous ; Adult ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/adverse effects ; Antibodies, Monoclonal, Humanized/pharmacokinetics ; Double-Blind Method ; Drug Administration Schedule ; Female ; Healthy Volunteers ; Humans ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Myostatin/antagonists & inhibitors ; Young Adult
Chemical Substances	Antibodies, Monoclonal, Humanized ; MSTN protein, human ; Myostatin ; domagrozumab (516MD5WQ24)
Language	English
Publishing date	2017-09-07
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.386
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Article ; Online: Impact of Acid-Reducing Agents on the Pharmacokinetics of Palbociclib, a Weak Base With pH-Dependent Solubility, With Different Food Intake Conditions.

Sun, Wan / Klamerus, Karen J / Yuhas, Lisa M / Pawlak, Sylvester / Plotka, Anna / O'Gorman, Melissa / Kirkovsky, Leonid / Kosa, Maha / Wang, Diane

Clinical pharmacology in drug development

2017 Volume 6, Issue 6, Page(s) 614–626

Abstract: Palbociclib free base capsule is a weak base drug with highly pH-dependent solubility. In vitro and in vivo studies evaluated the impact of acid-reducing agents on exposure of palbociclib and determined whether the impact, if any, can be mitigated by ... ...

Abstract	Palbociclib free base capsule is a weak base drug with highly pH-dependent solubility. In vitro and in vivo studies evaluated the impact of acid-reducing agents on exposure of palbociclib and determined whether the impact, if any, can be mitigated by food. A drug-drug interaction study (study 1) was conducted first under fasted conditions and showed that coadministration of multiple doses of the proton-pump inhibitor rabeprazole substantially reduced palbociclib mean area under the concentration-time curve from time 0 to infinity and maximum observed plasma concentration by 62% and 80%, respectively. In vitro assessment suggested that the presence of bile salt mixed micelles to mimic the fed state can significantly enhance the solubility of palbociclib. Subsequently, study 2 was conducted under fed conditions and demonstrated that coadministration of rabeprazole decreased palbociclib maximum observed plasma concentration by 41% but had limited impact on area under the concentration-time curve from 0 to infinity (13% decrease). This study also showed that the histamine-2 receptor antagonist famotidine and local antacid with staggered dosing had no impact on palbociclib exposure under fed conditions. Food intake effectively mitigated the impact of acid-reducing agents on palbociclib exposure. Palbociclib free base capsule should be taken with food, and acid-reducing agent use does not need to be avoided.
MeSH term(s)	Adult ; Antacids/administration & dosage ; Antacids/pharmacology ; Area Under Curve ; Bile Acids and Salts/chemistry ; Drug Administration Schedule ; Drug Interactions ; Famotidine/administration & dosage ; Famotidine/pharmacology ; Female ; Food-Drug Interactions ; Histamine H2 Antagonists/administration & dosage ; Histamine H2 Antagonists/pharmacology ; Humans ; Hydrogen-Ion Concentration ; Male ; Micelles ; Middle Aged ; Piperazines/administration & dosage ; Piperazines/chemistry ; Piperazines/pharmacokinetics ; Protein Kinase Inhibitors/administration & dosage ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacokinetics ; Proton Pump Inhibitors/administration & dosage ; Proton Pump Inhibitors/pharmacology ; Pyridines/administration & dosage ; Pyridines/chemistry ; Pyridines/pharmacokinetics ; Rabeprazole/administration & dosage ; Rabeprazole/pharmacology ; Solubility ; Young Adult
Chemical Substances	Antacids ; Bile Acids and Salts ; Histamine H2 Antagonists ; Micelles ; Piperazines ; Protein Kinase Inhibitors ; Proton Pump Inhibitors ; Pyridines ; Rabeprazole (32828355LL) ; Famotidine (5QZO15J2Z8) ; palbociclib (G9ZF61LE7G)
Language	English
Publishing date	2017-11
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	2649010-9
ISSN	2160-7648 ; 2160-763X
ISSN (online)	2160-7648
ISSN	2160-763X
DOI	10.1002/cpdd.356
Database	MEDical Literature Analysis and Retrieval System OnLINE

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