Pharmacokinetics and toxicology of therapeutic proteins: Advances and challenges

Table 1 Examples of proteins and peptides administered subcutaneously[10]

INN/BAN (description)	Trade name	MW (kDa)	Absolute bioavailability1	SC animal models used in drug development
Buserelin acetate (LH-releasing hormone analog)	Suprefact	1.30	Human: 70%	Pharm: rat, hamster, guinea pig, rabbit, dog and monkey Tox: mouse, rat, rabbit and dog
Pramlintide acetate (amylin analog)	Symlin	3.95	Human: 30 to 40%	Pharm: rat and dog PK: mouse, rat, rabbit and dog Tox: mouse, rat, rabbit and dog
Insulin lispro (insulin analog)	Humalog	5.81	Human: 55 to 77%	Pharm: rat, rabbit, dog and pig PK: rat and dog Tox: rat, rabbit and dog
Insulin glulisine (insulin analog)	Apidra	5.82	Human: about 70% Dog: 42% Rat: 96%2	Pharm: rat and dog PK: rat and dog Tox: mouse, rat, rabbit and dog
Insulin glargine (insulin analog)	Lantus	6.06	Precipitates in skin-slow uptake in human, dog and rat	Pharm: mouse, rat, guinea pig, rabbit and dog PK: rat and dog Tox: mouse, rat, guinea pig, rabbit and dog
Mecasermin (IGF-1)	Increlex	7.65	Human: about 100% Rabbit: 47% Rat: 38 to 57%	Pharm: mouse, rat, rabbit and monkey PK: rat, rabbit, dog and monkey Tox: rat, dog, rabbit and monkey
IFNβ-1b (cytokine)	Betaseron	18.5	Human: 50% Monkey: 31 to 44%	Pharm: monkey PK: monkey Tox: rabbit and monkey
Somatropin (GH)	Nutropin	22	Human: 81%	Pharm: rat PK: rat and monkey Tox: mouse, rat, dog and monkey
IFNβ-1a (cytokine)	Rebif	22.5	Human: 6 to 62% Monkey: 12 to 38% Rat: 16%	Pharm: mouse and monkey PK: rat and monkey Tox: monkey
PEG-IFNα-2b (cytokine variant)	PEG-Intron	31	Monkey: 57 to 89% Rat: 43 to 51%	Pharm: rat and monkey PK: rat and monkey Tox: mouse, rat, rabbit and monkey
Pegfilgrastim (PEG-G-CSF)	Neulasta	39	Monkey: 49 to 68% Rat: < 10% to 30%	Pharm: mouse, rat and dog PK: mouse, rat and monkey Tox: rat and monkey
Pegvisomant (PEG-GH)	Somavert	42, 47 and 523	Human: 49 to 65% Monkey: 70 to 81% Mouse: 45 to 73%	Pharm: mouse and monkey PK: mouse, rat, rabbit and monkey Tox: mouse, rat, rabbit and monkey
PEG-IFNα-2a (cytokine variant)	Pegasys	60	Human: 61 to 80%	Pharm: mouse PK: rat and monkey Tox: mouse, rat and monkey
Certolizumab pegol (PEG-anti-TNFα Fab' fragment)	Cimzia	91	Human: 76 to 88% Rat: 24 to 34%	PK: rat and monkey Tox: monkey
Canakinumab (anti-IL-1β mAb)	Ilaris	145	Human: 63 to 67% Monkey: 60%	Pharm: mouse, rat and monkey (marmoset) PK: mouse and monkey Tox: mouse and monkey
Adalimumab (anti-TNF mAb)	Humira	148	Human: 64% Monkey: 96%	PK: monkey Tox: rabbit and monkey
Omalizumab (anti-IgE mAb)	Xolair	149	Human: 53 to 71% Monkey: 64 to 104% Mouse: 90%	Pharm: monkey PK: mouse and monkey Tox: monkey
Golimumab (anti-TNF mAb)	Simponi	150	Human: 53% Monkey: 77%	PK: monkey Tox: mouse and monkey
Ustekinumab (anti-p40 mAb)	Stelara	150	Human: 24 to 95% Monkey: 97%	Pharm: monkey PK: monkey Tox: monkey
Etanercept (TNF receptor-Fc-IgG1 fusion protein)	Enbrel	150	Human: 76% Monkey: 73% Mouse: 58%	Pharm: mouse PK: mouse, rat and monkey Tox: mouse, rat, rabbit and monkey
Rilonacept (IL-1 inhibitor, fusion protein)	Arcalyst	251	Human: 43% Monkey: 70% Rat: 60% Mouse: 78%	Pharm: mouse and monkey PK: mouse, rat and monkey Tox: monkey

¹Systemic dose following subcutaneous (SC) injection relative to systemic dose following intravenous injection;

²Assumes linearity of AUC/dose;

³Product is a mixture of three distinct protein variants. GH: Growth hormone; LH: Luteinizing hormone; MW: Molecular weight; Pharm: Pharmacology; PK: Pharmacokinetics; Tox: Toxicology (including safety pharmacology); INN: International nonproprietary name; BAN: British approved name; SC: Subcutaneous; PEG: Polyethylene glycol; IFN: Interferon; TNF: Tumor necrosis factor; IL: Interleukin.