Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Peptides: When Is the Assessment of Certain Factors Warranted?
Abstract
:1. Introduction
- Number of amino acids making up the chain;
- Their source, animal or plant;
- Functions in the human body.
2. Pharmacokinetics of Peptides
2.1. Absorption
2.2. Distribution
2.3. Metabolism or Degradation and Elimination of Peptides
2.3.1. Blood
2.3.2. Liver
2.3.3. Kidney
2.3.4. Gastrointestinal Tract
- Luminally secreted enzymes as well as pepsins, trypsin, chymotrypsin, elastase, and carboxypeptidase A/B;
- Brush border membrane-bound enzymes;
- Cytoplasmic enzymes.
3. Strategies to Protect Peptides from Degradation (Proteolysis)
- Chemical modification of peptides at N- and/or C-terminus of a peptide. The chemical modification of a peptide can be achieved by N-acetylation and C-amidation. Tesamorelin is a hexenoyl moiety attached to the tyrosine residue at the N-terminus.
- Cyclization of linear peptides enhances the stability of these peptides in human serum. Furthermore, bicyclic peptides have higher proteolytic stability than the linear peptides and the cyclization of the peptide backbone improves stability.
- Nanoparticle formulations. Peptide-based nanomaterials consist of small peptide sequences that have a variety of properties. These nanomaterials have major advantages such as biocompatibility, high biological activity, bio-functionality, and easy modifiability. Peptide self-assembly is considered an effective method to improve the proteolytic stability of peptide drugs. Self-assembled peptide-based nanostructures such as tubes, filaments, fibrils, hydrogels, vesicles, and monolayers have been studied. Self-assembled lytic peptides have defined nanostructures and are protease-resistant. Nanostructures are developed from modified amino acids (N- or C-terminal modifications) to enhance cellular and in vivo stability. These modified nanostructures have shown enhanced drug delivery properties both under in vivo and in vitro conditions. Self-assembling peptides may be suitable for controlled release or targeting of anticancer drugs to tumor sites [22].
- Disulfide (DS) bridges help in the structural stabilization of peptides. Many peptides have more than one DS. Examples include lepirudin (65 amino acids, 3 DS), ziconotide (25 amino acids, 3 DS), calcitonin (32 amino acids, 1 DS), and linaclotide (14 amino acids, 3 DS). Three disulfide bridges make linaclotide stable enough for oral administration.
- Conjugation with polymers such as polyethylene glycol (PEG), conjugation to Fc antibody portion, and albumin fusion help in increasing the half-lives of peptides.
4. Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Peptides
5. Age (Elderly (65 Years and Older) versus Young) (Table 2)
6. Sex and Race (Table 2)
7. Pediatrics (Table 2)
8. Renal Impairment (Table 3)
9. Hepatic Impairment (Table 3)
10. Drug Interaction Studies (Table 3)
11. Immunogenicity (Table 4)
12. Pregnancy (Table 4)
13. Lactation (Table 4)
14. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Vlieghe, P.; Lisowski, V.; Martinez, J.; Khrestchatisky, M. Synthetic therapeutic peptides: Science and market. Drug Discov. Today 2010, 15, 40–56. [Google Scholar] [CrossRef]
- Lau, J.L.; Dunn, M.K. Therapeutic peptides: Historical perspectives, current development trends, and future directions. Bioorg. Med. Chem. 2018, 26, 2700–2707. [Google Scholar] [CrossRef] [PubMed]
- Derakhshankhah, H.; Jafari, S. Biomedicine & Pharmacotherapy Cell-penetrating peptides: A concise review with emphasis on biomedical applications. Biomed. Pharmacother. 2018, 108, 1090–1096. [Google Scholar] [PubMed]
- Marqus, S.; Pirogova, E.; Piva, T.J. Evaluation of the use of therapeutic peptides for cancer treatment. J. Biomed. Sci. 2017, 24, 21. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Malonis, R.J.; Lai, J.R.; Vergnolle, O. Peptide-Based Vaccines: Current Progress and Future Challenges. Chem. Rev. 2020, 120, 3210–3229. [Google Scholar] [CrossRef] [Green Version]
- La Manna, S.; Di Natale, C.; Florio, D.; Marasco, D. Peptides as therapeutic agents for inflammatory-related diseases. Int. J. Mol. Sci. 2018, 19, 2714. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- FDA. FDA Calls for Input on Peptide Evaluation. Posted on 13 May 2021. Available online: https://www.raps.org/news-and-articles/news-articles/2021/5/fda-calls-for-input-on-peptide-evaluation (accessed on 25 August 2021).
- Tang, L.; Persky, A.; Hochhaus, G.; Meibohm, B. Pharmacokinetic aspects of biotechnology products. J. Pharm. Sci. 2004, 93, 2184–2204. [Google Scholar] [CrossRef]
- Diao, L.; Meibohm, B. Pharmacokinetics and Pharmacokinetic–Pharmacodynamic Correlations of Therapeutic Peptides. Clin. Pharmacokinet. 2013, 52, 855–868. [Google Scholar] [CrossRef]
- McMartin, C. Pharmacokinetics of Peptides and Proteins: Opportunities and Challenges. Adv. Drug Res. 1992, 22, 39–106. [Google Scholar] [CrossRef]
- Bumbaca, B.; Li, Z.; Shah, D.K. Pharmacokinetics of protein and peptide conjugates. Drug Metab. Pharmacokinet. 2019, 34, 42–54. [Google Scholar] [CrossRef]
- Datta-Mannan, A. Mechanisms Influencing the Pharmacokinetics and Disposition of Monoclonal Antibodies and Peptides. Drug Metab. Dispos. 2019, 47, 1100–1110. [Google Scholar] [CrossRef] [Green Version]
- Lin, J.H. Pharmacokinetics of Biotech Drugs: Peptides, Proteins and Monoclonal Antibodies. Curr. Drug Metab. 2009, 10, 661–691. [Google Scholar] [CrossRef]
- Richter, W.; Bhansali, S.G.; Morris, M.E. Mechanistic Determinants of Biotherapeutics Absorption Following SC Administration. AAPS J. 2012, 14, 559–570. [Google Scholar] [CrossRef] [Green Version]
- Porter, C.J.; Edwards, G.A.; Charman, S.A. Lymphatic transport of proteins after SC injection: Implications of animal model selection. Adv Drug Deliv Rev. 2001, 50, 157–171. [Google Scholar] [CrossRef]
- Singh, R.; Singh, S.; Lillard, J.W. Past, Present, and Future Technologies for Oral Delivery of Therapeutic Proteins. J. Pharm. Sci. 2008, 97, 2497–2523. [Google Scholar] [CrossRef] [Green Version]
- Mahato, R.I.; Narang, A.S.; Thoma, L.; Miller, D.D. Emerging Trends in Oral Delivery of Peptide and Protein Drugs. Crit. Rev. Ther. Drug Carr. Syst. 2003, 20, 153–214. [Google Scholar] [CrossRef]
- Karsdal, M.A.; Henriksen, K.; Bay-Jensen, A.C.; Molloy, B.; Arnold, M.; John, M.R.; Byrjalsen, I.; Azria, M.; Riis, B.J.; Qvist, P.; et al. Lessons Learned From the Development of Oral Calcitonin: The First Tablet Formulation of a Protein in Phase III Clinical Trials. J. Clin. Pharmacol. 2011, 51, 460–471. [Google Scholar] [CrossRef]
- Antosova, Z.; Mackova, M.; Král, V.; Macek, T. Therapeutic application of peptides and proteins: Parenteral forever? Trends Biotechnol. 2009, 27, 628–635. [Google Scholar] [CrossRef] [PubMed]
- Senel, S.; Kremer, M.; Katalin, N.; Squier, C. Delivery of Bioactive Peptides and Proteins Across Oral (Buccal) Mucosa. Curr. Pharm. Biotechnol. 2001, 2, 175–186. [Google Scholar] [CrossRef] [PubMed]
- Di, L. Strategic Approaches to Optimizing Peptide ADME Properties. AAPS J. 2015, 17, 134–143. [Google Scholar] [CrossRef] [PubMed]
- Yao, J.-F.; Yang, H.; Zhao, Y.-Z.; Xue, M. Metabolism of Peptide Drugs and Strategies to Improve their Metabolic Stability. Curr. Drug Metab. 2018, 19, 892–901. [Google Scholar]
- Murphey, L.J.; Hachey, D.L.; Oates, J.A.; Morrow, J.D.; Brown, N.J. Metabolism of bradykinin in vivo in humans: Identification of BK1-5 as a stable plasma peptide metabolite. J. Pharmacol. Exp. Ther. 2000, 294, 263–269. [Google Scholar]
- Zhu, L.; Tamvakopoulos, C.; Xie, D.; Dragovic, J.; Shen, X.; Fenyk-Melody, J.E.; Schmidt, K.; Bagchi, A.; Griffin, P.R.; Thornberry, N.A.; et al. The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides in vivo metabolism of pituitary adenylate cyclase-activating polypeptide-(1–38). J. Biol. Chem. 2003, 278, 22418–22423. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abid, K.; Rochat, B.; Lassahn, P.G.; Stöcklin, R.; Michalet, S.; Brakch, N.; Aubert, J.F.; Vatansever, B.; Tella, P.; De Meester, I.; et al. Kinetic study of Neuropeptide Y (NPY) proteolysis in blood and identification of NPY3-35 a new peptide generated by plasma kallikrein. J. Biol. Chem. 2009, 284, 24715–24724. [Google Scholar] [CrossRef] [Green Version]
- Baumann, A. Early Development of Therapeutic Biologics—Pharmacokinetics. Curr. Drug Metab. 2006, 7, 15–21. [Google Scholar] [CrossRef] [PubMed]
- Authier, F.; Posner, B.I.; Bergeron, J.J. Endosomal proteolysis of internalized proteins. FEBS Lett. 1996, 389, 55–60. [Google Scholar] [CrossRef] [Green Version]
- Serada, M.; Sakurai-Tanikawa, A.; Igarashi, M.; Mitsugi, K.; Takano, T.; Shibusawa, K.; Kohira, T. The role of the liver and kidneys in the pharmacokinetics of subcutaneously administered teriparatide acetate in rats. Xenobiotica 2012, 42, 398–407. [Google Scholar] [CrossRef]
- Wilkinson, G.R. The effects of diet aging and disease-states on presystemic elimination and oral drug bioavailability in humans. Adv. Drug Deliv. Rev. 1997, 27, 129–159. [Google Scholar] [CrossRef]
- Busby, R.W.; Kessler, M.M.; Bartolini, W.P.; Bryant, A.P.; Hannig, G.; Higgins, C.S.; Solinga, R.M.; Tobin, J.V.; Wakefield, J.D.; Kurtz, C.B.; et al. Pharmacologic properties, metabolism, and disposition of Linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J. Pharm. Exp. Ther. 2013, 34, 196–206. [Google Scholar] [CrossRef] [Green Version]
- Wacher, V.J.; Silverman, J.A.; Zhang, Y.; Benet, L.Z. Role of P-Glycoprotein and Cytochrome P450 3A in Limiting Oral Absorption of Peptides and Peptidomimetics. J. Pharm. Sci. 1998, 87, 1322–1330. [Google Scholar] [CrossRef]
- FDA Package Insert IMCIVREE (Setmelanotide). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213793s000lbl.pdf (accessed on 20 August 2021).
- FDA Package Insert SCENESSE (Afamelanotide). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210797s000lbl.pdf (accessed on 20 August 2021).
- FDA Package Insert VYLEESI (Bremelanotide Injection). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210557s000lbl.pdf (accessed on 20 August 2021).
- FDA Package Insert LUTATHER (Lutetium Lu 177 Dotatate). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208700s010lbl.pdf (accessed on 20 August 2021).
- FDA Package Insert GIAPREZA (Angiotensin II). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209360s000lbl.pdf (accessed on 20 August 2021).
- FDA Package Insert MACRILEN (Macimorelin). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/205598s000lbl.pdf (accessed on 20 August 2021).
- FDA Package Insert OZEMPIC (Semaglutide). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209637lbl.pdf (accessed on 25 August 2021).
- FDA Package Insert PARSABIV (Etelcalcetide). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208325Orig1s000Lbledt.pdf (accessed on 25 August 2021).
- FDA Package Insert TRULANCE (Plecanatide). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208745lbl.pdf (accessed on 25 August 2021).
- FDA Package Insert TYMLOS (Abaloparatide). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208743lbl.pdf (accessed on 25 August 2021).
- FDA Package Insert ADLYXIN (Lixisenatide). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208471Orig1s000lbl.pdf (accessed on 25 August 2021).
- FDA Package Insert TRESIBA (Insulin Degludec). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/203314lbl.pdf (accessed on 27 August 2021).
- FDA Package Insert NINLARO (Ixazomib). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/208462lbl.pdf (accessed on 27 August 2021).
- FDA Package Insert BLENREP (Belantamab Mafodotin-Blmf). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761158s000lbl.pdf (accessed on 25 August 2021).
- FDA Package Insert PADCEV (Enfortumab Vedotin-Ejfv). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761137s000lbl.pdf (accessed on 25 August 2021).
- FDA Package Insert POLIVY (Polatuzumab Vedotin-Piiq). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761121s000lbl.pdf (accessed on 25 August 2021).
- Biester, T.; Blaesig, S.; Remus, K.; Aschemeier, B.; Kordonouri, O.; Granhall, C.; Søndergaard, F.; Kristensen, N.R.; Haahr, H.; Danne, T. Insulin degludec’s ultra-long pharmacokinetic properties observed in adults are retained in children and adolescents with type 1 diabetes. Pediatric Diabetes 2014, 15, 27–33. [Google Scholar] [CrossRef] [PubMed]
- Meibohm, B.; Zhou, H. Characterizing the Impact of Renal Impairment on the Clinical Pharmacology of Biologics. J. Clin. Pharmacol. 2012, 52, 54S–62S. [Google Scholar] [CrossRef] [PubMed]
- Czock, D.; Keller, F.; Seidling, H.M. Pharmacokinetic predictions for patients with renal impairment: Focus on peptides and protein drugs. Br. J. Clin. Pharmacol. 2012, 74, 66–74. [Google Scholar] [CrossRef] [Green Version]
- Jacobsen, L.V.; Hindsberger, C.; Robson, R.; Zdarvkovic, M. Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br. J. Clin. Pharmacol. 2009, 68, 898–905. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Knudsen, L.B.; Lau, J. The Discovery and Development of Liraglutide and Semaglutide. Front. Endocrinol. 2019, 10, 155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Flint, A.; Nazzal, K.; Jagielski, P.; Hindsberger, C.; Zdarvkovic, M. Influence of hepatic impairment on pharmacokinetics of the human GLP-1 analogue, liraglutide. Br. J. Clin. Pharmacol. 2010, 70, 807–814. [Google Scholar] [CrossRef]
- Sun, Q.; Seo, S.; Zvada, S.; Liu, C.; Reynolds, K. Does Hepatic Impairment Affect the Exposure of Monoclonal Antibodies? Clin. Pharmacol. Ther. 2020, 107, 1256–1262. [Google Scholar] [CrossRef] [PubMed]
- FDA Package Insert VICTOZA (Liraglutide). Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/022341s027lbl.pdf (accessed on 25 August 2021).
- Mahmood, I.; Green, M.D. Drug Interaction Studies of Therapeutic Proteins or Monoclonal Antibodies. J. Clin. Pharmacol. 2007, 47, 1540–1554. [Google Scholar] [CrossRef]
Trade Name (Active Ingredient) | FDA Approval | Indication | Target Receptor | |
---|---|---|---|---|
Imcivree (setmelanotide) | 2020 | Obesity | Melanocortin-4 receptor | |
Scenesse (afamelanotide) | 2019 | Erythropoietic protoporphyria | Melanocortin 1 receptor | |
Vyleesi (bremelanotide injection) | 2019 | Hypoactive sexual desire disorder | Melanocortin receptors | |
Lutathera (lutetium Lu 177 dotatate) | 2018 | Gastroenteropancreatic neuroendocrine tumors | Somatostatin receptor | |
Giapreza (angiotensin II) | 2017 | Septic shock, diabetes mellitus, and acute renal failure | Type-1 angiotensin II receptor | |
Macrilen (macimorelin) | 2017 | Diagnosis of adult growth hormone deficiency | Growth hormone secretagogue receptor type 1 | |
Ozempic (semaglutide) | 2017 | Diabetes type (II) | Glucagon-like peptide 1 receptor | |
Parsabiv (etelcalcetide) | 2017 | Secondary hyperparathyroidism in adult chronic kidney disease | Calcium-sensing receptor | |
Trulance (plecanatide) | 2017 | Chronic idiopathic constipation | Guanylate cyclase-C | |
Tymlos (abaloparatide) | 2017 | Anabolic agent | Parathyroid hormone 1 receptor | |
Adlyxin (lixisenatide) | 2016 | Diabetes type (II) | Glucagon-like peptide 1 receptor | |
Tresiba (insulin degludec) | 2015 | Diabetes type (II) | Glucagon-like peptide 1 receptor | |
Ninlaro (ixazomib) | 2015 | Multiple myeloma | Beta 5 subunit of the 20S proteasome | |
Peptides in Antibody–Drug Conjugates | ||||
Blenrep (belantamab mafodotin-blmf) | 2020 | Relapsed or refractory multiple myeloma | B-cell maturation antigen (BCMA) | |
Polivy (polatuzumab vedotin-piiq) | 2019 | Refractory diffuse large B-cell lymphoma | CD79b receptor expressed in mature B-cells | |
Padcev (enfortumab vedotin-ejfv) | 2019 | Urothelial cancers | Nectin-4 receptor |
Peptides | Age (Young vs. Elderly) | Sex | Race | Pediatrics |
---|---|---|---|---|
Imcivree (setmelanotide) | The effect of age 65 years or older not known. | No clinically significant differences in the PK. | No information provided. It should be interpreted as unknown. | AUC and Cmax were 100% and 92% higher in children 6 to <12 years of age than adults. |
Scenesse (afamelanotide) | No information provided. | No information provided. | No information provided. | No information provided. |
Vyleesi (bremelanotide injection) | No information provided. | No information provided. | No information provided. | No information provided. |
Lutathera (lutetium Lu 177 dotatate) | The response rate and number of patients with a serious adverse event were similar to those of younger subjects. | No information provided. | No information provided. | No information provided. |
Giapreza (angiotensin II) | No significant difference in safety or efficacy between patients <65 and >65 years of age. | No significant difference in PK. | No information provided. | No information provided. |
Macrilen (macimorelin) | Not enough patients to evaluate the difference in response between patients <65 and >65 years of age. | No information provided. | No information provided. | No information provided. |
Ozempic (semaglutide) | No clinically meaningful effect on the PK. No significant difference in safety or efficacy between patients <65 and >65 years of age. | No clinically meaningful effect on the PK. | No clinically meaningful effect on the PK. African Americans, Asians, and Hispanics. | No information provided. |
Parsabiv (etelcalcetide) | No influence on the PK (age = 20–93 years). | No influence on the PK. | No influence on the PK. | No information provided. |
Trulance (plecanatide) | Not enough patients to evaluate the difference in response between patients <65 and >65 years of age. | No information provided. | No information provided. | Contraindicated in pediatric patients <6 years of age. Avoid use of Trulance in patients 6 years to <18 years of age. |
Tymlos (abaloparatide) | No age-related differences in the PK were observed in postmenopausal women 49 to 86 years of age. | Not applicable. Postmenopausal women with osteoporosis. | No impact on the PK. | No information provided. |
Adlyxin (lixisenatide) | No difference in safety and efficacy between patients <65 and >65 years of age. | No meaningful effect on the PK. | No meaningful effect on the PK. | No information provided. |
Tresiba (insulin degludec) | No difference in the PK and PD between patients <65 and >65 years of age. | No clinically meaningful effect on the PK. | No statistically significant differences in the PK and PD of Tresiba between African Americans, White Hispanics, and non-Hispanics. | After adjusting for body weight, the total exposure of Tresiba at steady state was independent of age (1 to <18 years of age). |
Ninlaro (ixazomib) | No clinically meaningful effect on clearance (CL) (age = 23–91 years). No difference in safety and efficacy between patients <65 and >65 years of age. | No clinically meaningful effect on CL. | No clinically meaningful effect on CL. | No information provided. |
Peptides in Antibody–Drug Conjugates | ||||
Blenrep (belantamab mafodotin-blmf) | No clinically significant differences in the PK. | No clinically significant differences in the PK. | No clinically significant differences in the PK. | No information provided. |
Polivy (polatuzumab vedotin-piiq) | No clinically significant differences in the PK. | No clinically significant differences in the PK. | No clinically significant differences in the PK. | No information provided. |
Padcev (enfortumab vedotin-ejfv) | No clinically significant differences in the PK. | No clinically significant differences in the PK. | No clinically significant differences in the PK. | No information provided. |
Peptides | Hepatic Impairment (HI) | Renal Impairment (RI) | Drug Interaction |
---|---|---|---|
Imcivree (setmelanotide) | No information provided. | A 19% higher AUC in patients with mild RI than patients with normal renal function. Not for use in patients with moderate, severe RI, and end-stage renal disease (ESRD). | In vitro study of drug–drug interactions indicated that setmelanotide has low potential for PK drug–drug interactions related to cytochrome P450 (CYP 450) and transporters. No clinical studies evaluating the drug–drug interaction potential of setmelanotide were conducted. |
Scenesse (afamelanotide) | No information provided. | No information provided. | No information provided |
Vyleesi (bremelanotide injection) | Following a single SC dose of Vyleesi, the AUC increased 1.2-fold and 1.7-fold, with mild and moderate HI. No information available for severe HI. | Following a single SC dose of Vyleesi, the AUC increased by 1.2-fold, 1.5-fold, and 2-fold in patients with mild, moderate, and severe RI. | Vyleesi may slow gastric emptying and thus has the potential to reduce the rate and extent of absorption of concomitantly administered oral medications. Vyleesi reduced the Cmax and AUC for naltrexone and indomethacin by 40–60% and 20 to 40%, respectively. |
Lutathera (lutetium Lu 177 dotatate) | No dose adjustment was recommended for patients with mild to moderate HI (reason for this is not known). No information on severe HI. | No dose adjustment was recommended for patients with mild to moderate RI (reason for this is not known). No information on severe RI or ESRD. | The nonradioactive form of lutetium is not an inhibitor or inducer of cytochrome P450 enzymes in vitro (1A2, 2B6, 2C9, 2C19, or 2D6). It is also not an inhibitor of P-glycoprotein, BCRP, OAT1, OAT3, OCT2, OATP1B1, OATP1B3, or OCT1 in vitro. |
Giapreza (angiotensin II) | No PK study was conducted with Giapreza because its clearance is not dependent on hepatic function. | No PK study was conducted with Giapreza because its clearance is not dependent on renal function. | Concomitant use of angiotensin-converting enzyme (ACE) inhibitors may increase the response to Giapreza, whereas concomitant use of angiotensin II blockers may decrease the response to Giapreza. |
Macrilen (macimorelin) | No information provided. | No information provided. | Coadministration of Macrilen with drugs that prolong the QT interval may lead to development of torsade de pointes-type ventricular tachycardia. Coadministration of a strong CYP3A4 inducer with Macrilen may reduce the plasma Macrilen concentrations. |
Ozempic (semaglutide) | No dose adjustment of Ozempic is needed for patients with mild, moderate, and severe HI. The source of this information is not known. | No dose adjustment of Ozempic is needed for patients with mild, moderate, and severe RI. The source of this information is not known. | Ozempic causes a delay of gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. |
Parsabiv (etelcalcetide) | No information provided. | No information provided. | Etelcalcetide did not inhibit or induce CYP450 enzymes and is not a substrate of CYP450 enzymes. Etelcalcetide was not a substrate of efflux and uptake transporter of P-glycoprotein (Pgp). |
Trulance (plecanatide) | No information provided. | No information provided. | In vitro studies indicated that plecanatide and its active metabolite do not inhibit or induce CYP3A4. Plecanatide and its active metabolite are neither substrates nor inhibitors of Pgp. |
Tymlos (abaloparatide) | No information provided. | A PK study indicated that Cmax and AUC of Tymlos increased by 1.4- and 2.1-fold, respectively, in subjects with severe RI as compared to subjects with normal renal function. No dosage adjustment is required for patients with mild, moderate, or severe RI. | No specific drug–drug interaction studies were performed. In vitro studies indicated that Tymlos does not inhibit or induce CYPP450 enzymes. |
Adlyxin (lixisenatide) | No PK study was performed in patients with HI. HI is not expected to affect the PK of lixisenatide. | Compared to healthy subjects, plasma Cmax and AUC of lixisenatide increased by 60%, 42%, and 83% and 34%, 69%, and 124% in subjects with mild, moderate, and severe RI, respectively. No dose adjustment in patients with RI was recommended. | Drug interaction studies of lixisenatide were conducted with acetaminophen, oral contraceptives, warfarin, atorvastatin, digoxin, and ramipril. The results were variable and changes in Cmax and AUC were time-dependent. |
Tresiba (insulin degludec) | No difference in the PK of Tresiba following an SC dose of 0.4 units/kg was noted between healthy subjects and subjects with HI (mild, moderate, and severe). | The PK of Tresiba following an SC dose of 0.4 units/kg was studied in subjects with mild, moderate, and severe RI. Total AUC and Cmax were about 10–25% and 13–27% higher, respectively, in subjects with mild to severe RI. In subjects with ESRD, the exposure of Tresiba was similar to subjects with normal renal function. | A number of medications affect glucose metabolism and may require insulin dose adjustment and close monitoring. The package insert identifies several classes of drugs that may produce clinically significant drug interactions with Tresiba.
|
Ninlaro (ixazomib) | In patients with moderate or severe HI, the mean AUC increased by 20% as compared to patients with normal hepatic function. | The PK of ixazomib was similar in patients with normal renal function and in patients with mild or moderate RI. Mean AUC was 39% higher in patients with severe RI or in patients with ESRD requiring dialysis as compared to patients with normal renal function. | Coadministration of Ninlaro with rifampin (a strong CYP3A Inducer) decreased ixazomib Cmax and AUC by 54% and 74%, respectively. Coadministration of Ninlaro with clarithromycin (strong CYP3A Inhibitors) and strong CYP1A2 inhibitors did not result in a clinically meaningful change in the systemic exposure of ixazomib. Ninlaro is not expected to produce drug–drug interactions via CYP inhibition or induction. Ixazomib is a low-affinity substrate of P-gp. |
Blenrep (belantamab mafodotin-blmf) | Mild HI had no impact on the PK of Blenrep. The impact of moderate and severe HI on the PK of Blenrep is not known. | Mild or moderate RI had impact on the PK of Blenrep. The impact of severe RI or ESRD with or without dialysis on the PK of Blenrep is not known. | Monomethyl auristatin F (MMAF), a payload, is a substrate of organic anion transporting polypeptide (OATP)1B1 and OATP1B3, multidrug resistance-associated protein (MRP)1, MRP2, MRP3, bile salt export pump (BSEP), and a possible substrate of P-gp. |
Polivy (polatuzumab vedotin-piiq) 2019 | In patients with mild HI, the PK of monomethyl auristatin E (MME) was similar between patients with normal hepatic function but unconjugated MME was higher by 40% in subjects with HI. The impact of moderate and severe hepatic impairment or liver transplantation on the PK of MME is not known. | No difference in the PK of conjugated and unconjugated MME was noted between patients with mild or moderate RI and normal renal function. The impact of severe RI and in patients with ESRD on the PK of MME is not known. | No dedicated drug–drug interaction clinical study of Polivy was conducted. POPPK analysis indicated that concomitant rituximab was associated with increased conjugated MMAE AUC by 24% and decreased unconjugated MMAE AUC by 37%. |
Padcev (enfortumab vedotin-ejfv) 2019 | POPPK study indicated that there was a 48% increase in the AUC of unconjugated MMAE in patients with mild HI as compared to subjects with normal hepatic function. The effect of moderate or severe HI on the PK of Padcev or unconjugated MMAE is not known. | Following 1.2 mg/kg dose of Padcev, mild, moderate, and severe RI impairment had no impact on the PK of Padcev or unconjugated MMAE. The effect of end-stage renal disease with or without dialysis on the PK of Padcev or unconjugated MMAE is not known. | Drug–drug interaction studies of Padcev have not formally been evaluated. Ketoconazole (a strong CYP3A4 inhibitor) increased MMAE Cmax by 25% and AUC by 34%. Rifampin (a strong CYP3A4 inducer) decreased MMAE Cmax by 44% and AUC by 46%. |
Peptides | Pregnancy | Lactation | Immunogenicity |
---|---|---|---|
Imcivree (setmelanotide) | The FDA package insert states “Discontinue Imcivree when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus”. There are no available data with Imcivree in pregnant women to inform a drug-associated risk for major birth defects and miscarriage, or adverse maternal or fetal outcomes. | Treatment with Imcivree is not recommended for use while breastfeeding. There is no information on the presence of setmelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. | Approximately 61% of adult and pediatric patients who received Imcivree (n = 28) were positive for antibodies to Imcivree Lack of decline in Imcivree concentrations to suggest the presence of antidrug antibodies. |
Scenesse (afamelanotide) | No information provided. | No information provided. | No information provided. |
Vyleesi (bremelanotide injection) | There are not enough data in pregnant women to determine a drug-associated risk of adverse effects, major birth defects, miscarriage, or adverse maternal or fetal outcomes. | There is no information on the presence of bremelanotide or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. | No information provided. |
Lutathera (lutetium Lu 177 dotatate) | Based on its mechanism of action, Lutathera can cause fetal harm. There are no available data on Lutathera use in pregnant women. | There are no data on the presence of lutetium Lu 177 dotatate in human milk or its effects on the breastfed infant or milk production. | No information provided. |
Giapreza (angiotensin II) | There are not enough data in pregnant women to determine a drug-associated risk of adverse effects. | It is not known whether Giapreza is present in human milk. No data are available on the effects of Giapreza on the breastfed child or the effects on milk production. | No information provided. |
Macrilen (macimorelin) | There are no available data with Macrilen use in pregnant women to inform a drug-associated risk for adverse effects. | There are no data on the presence of macimorelin in human milk, the effects on the breastfed infant, or the effects on milk production. | No information provided. |
Ozempic (semaglutide) | There are limited data with semaglutide use in pregnant women to assess drug-associated risk for adverse effects. Ozempic should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. | There are no data on the presence of semaglutide in human milk, the effects on the breastfed infant, or the effects on milk production. | Across the placebo- and active-controlled glycemic control trials, 32 (1.0%) Ozempic-treated patients developed antidrug antibodies. |
Parsabiv (etelcalcetide) | There are no available data on the use of Parsabiv in pregnant women. | There are no data regarding the presence of Parsabiv in human milk or effects on the breastfed infant or on milk production. | Patients (7.1%) with secondary hyperparathyroidism treated with etelcalcetide for up to 6 months tested positive for binding anti-etelcalcetide antibodies. |
Trulance (plecanatide) | There are not enough data in pregnant women to assess any drug-associated risks for major birth defects and miscarriage. Since plecanatide and its active metabolite are negligibly absorbed following oral administration, maternal use is not expected to result in fetal exposure to the drug. | There is no information regarding the presence of plecanatide in human milk or its effects on milk production or the breastfed infant. | No information provided. |
Tymlos (abaloparatide) | Tymlos is not indicated for use in females of reproductive potential. There are no human data with Tymlos use in pregnant women to assess any drug-associated risks. | There is no information on the presence of abaloparatide in human milk, the effects on the breastfed infant, or the effects on milk production | Following 18 months of Tymlos treatment, 49% of subjects developed anti-abaloparatide antibodies; of these, 68% developed neutralizing antibodies to abaloparatide. |
Adlyxin (lixisenatide) | There are not enough data with lixisenatide in pregnant women to assess the risk of major birth defects and miscarriage. | There is no information regarding the presence of Adlyxin in human milk, the effects on the breastfed infant, or the effects on milk production. | Seventy percent of patients exposed to lixisenatide tested positive for anti-lixisenatide antibodies. No information regarding the presence of neutralizing antibodies is available. |
Tresiba (insulin degludec) | There are no available data with Tresiba in pregnant women about drug-associated risk for major birth defects and miscarriage. | There are no data on the presence of insulin degludec in human milk, the effects on the breastfed infant, or the effects on milk production. | In adult type 1 diabetic patients, 95.9% were positive for anti-insulin antibodies (AIA) at least once during the studies, including 89.7% that were positive at baseline. In studies of type 2 diabetic patients, 31.5% of patients were positive for AIA at least once during the studies, including 14.5% that were positive at baseline. |
Ninlaro (ixazomib) | Ninlaro can cause fetal harm when administered to a pregnant woman. There are no human data available regarding the effect of Ninlaro on pregnancy or development of the embryo or fetus. | It is not known whether Ninlaro or its metabolites are present in human milk. | No information provided. |
Polivy (polatuzumab vedotin-piiq), | There are no available data on the use of Polivy in pregnant women to evaluate for drug-associated risk, risk of major birth defects, and miscarriage. | There are no data on the presence of Polivy in human milk or the effects on the breastfed child or milk production. | Across all studies, 8 out of 134 (6%) patients were tested positive for antibodies against Polivy at one or more post-baseline time points. |
Blenrep (belantamab mafodotin-blmf), | Based on its mechanism of action, Blenrep can cause fetal harm when administered to a pregnant woman, because it contains a genotoxic compound (the microtubule inhibitor MMAF) and it targets actively dividing cells. There are no available data on the use of Blenrep in pregnant women to evaluate for drug-associated risk. | There are no data on the presence of belantamab mafodotin-blmf in human milk or the effects on the breastfed child or milk production. | In clinical studies of Blenrep, 2/274 patients (<1%) tested positive for anti-Blenrep antibodies after treatment. |
Padcev (enfortumab vedotin-ejfv), | There are no available data on the use of Padcev in pregnant women to evaluate for drug-associated risk, major birth defects, and miscarriage. | There are no data on the presence of Padcev in human milk or the effects on the breastfed child or milk production. | Out of 365 patients evaluated for immunogenicity to Padcev, 4 patients (1%) were found to be transiently positive for anti-Padcev antibody. |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Mahmood, I.; Pettinato, M. Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Peptides: When Is the Assessment of Certain Factors Warranted? Antibodies 2022, 11, 1. https://doi.org/10.3390/antib11010001
Mahmood I, Pettinato M. Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Peptides: When Is the Assessment of Certain Factors Warranted? Antibodies. 2022; 11(1):1. https://doi.org/10.3390/antib11010001
Chicago/Turabian StyleMahmood, Iftekhar, and Mark Pettinato. 2022. "Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Peptides: When Is the Assessment of Certain Factors Warranted?" Antibodies 11, no. 1: 1. https://doi.org/10.3390/antib11010001
APA StyleMahmood, I., & Pettinato, M. (2022). Impact of Intrinsic and Extrinsic Factors on the Pharmacokinetics of Peptides: When Is the Assessment of Certain Factors Warranted? Antibodies, 11(1), 1. https://doi.org/10.3390/antib11010001