Table 7.

Summary of reported RBC-associated drug pharmacokinetic parameters.

Drug	Species	Condition	PK Changes	Pharmacologic Effect (Relative to Free Drug)	References
5-Fluoruracil (5-FU)	Mouse	Malignant Ascites	2-fold increase in AUC0-inf in ascites fluid	70% survival at 20 days vs. 20% in malignant ascites model	[79]
Adenosine Deaminase (ADA)	Human	ADA Deficiency	2–4-fold increase in ADA t1/2 57-day lifespan of loaded RBC		[80]
Alcohol Dehydrogenase (ADH) Aldehyde Dehydrogenase (ALDH)	Mouse	Healthy	4.5-day RBC t1/2	43% reduction in blood ethanol concentrations vs. empty RBC	[81]
Amikacin	Rat	Healthy	2-fold increase in AUC0-inf in plasma Large increases in liver/spleen AUC0-inf		[82,83]
Carbonic Anhydrase	Rat	Healthy	Similar circulation time as carrier RBC 9-day t1/2 of loaded RBC		[84]
Daunorubicin	Human	Acute Leukemia	~2-fold increase in blood t1/2		[85]
Dexamethasone	Human Human Human Rabbit	Inflammatory Bowel Disease Chronic Obstructive Pulmonary Disease Cystic Fibrosis Healthy	Plasma concentrations detectable 28 days post-infusion Plasma concentrations detectable for at least 1 week post-infusion Relatively constant plasma concentrations for at least 10 days ~60-fold increase in plasma t1/2	50% reduction in ESR and CRP relative to standard of care Reduction in ‘as-needed’ use of corticosteroids and β-agonists Improved FEV1 and 51% reduction in antibiotic use Reduction in histamine response	[86,87,88,89,90]
Doxorubicin	Human	Lymphoma	2-7-fold increase in plasma t1/2		[91]
Erythropoietin	Mouse	Healthy	~5-fold increase in blood AUC 5.6 day RBC t1/2	~2-fold increase in 59Fe incorporation into circulating RBC	[92]
Factor IX	Human	Healthy	~8-fold increase in blood t12		[93]
Gentamicin	Human	Healthy	22 day blood t1/2		[94]
Imidocarb	Mouse	Parasitemia	Significantly increased blood concentrations	~25% reduction in peak parasitemia	[95]
Indinavir	Rat	Healthy	9-fold increase in plasma AUC0-inf		[96]
L-Asparaginase	Mouse Mouse Mouse	Healthy Healthy Acute Lymphoblastic Leukemia	~3-fold increase in blood t1/2 9–10.6 day RBC t1/2 16-fold increase in blood t1/2 2.4–4 day blood t1/2	4–5-fold increase in duration of maximal asparagine lowering >10-fold increase in duration of total asparagine suppression Reduced ADA formation 44% increase in survival time vs. untreated	[42,97,98]
Maltose-Binding Protein	Mouse	Healthy	~3-fold increase in blood t1/2		[15]
Methotrexate	Mouse	Healthy	3.5-fold increase in plasma t1/2 ~2-fold increase in liver and spleen uptake		[99]
Phenylalanine Hydroxylase	Mouse	Naive	Detectable drug in blood for at least 10 days post-injection vs. <6 h	~50% reduction in blood Phe vs. 25%	[100]
Prednisolone	Rat	Healthy	High drug uptake in liver		[101]
Polystyrene Nanoparticles	Mouse	Healthy	2–3-fold increase in blood exposure ~5-fold increase in lung uptake >50% decrease in spleen uptake No effect on RBC survival (t1/2 = 33.5 h)		[58]
Reteplase	Mouse	Acute Thrombosis	Blood t1/2 of ~10 h vs. minutes No impact on RBC circulation time	~3-fold delay in time to arterial occlusion Complete prevention of venous occlusion	[18]
Rhodanese	Mouse	Healthy	230-fold increase in t1/2	40% reduction in blood cyanide following IV injection	[102]
Tissue Plasminogen Activator	Mouse Rat	Acute Thrombosis Acute Thrombosis	~10-fold increase in blood exposure No changes in RBC survival >10-fold increase in blood AUC Minimal effects on RBC circulation	~50% lysis of pulmonary emboli Significant reduction in mortality from thromboembolic stroke ~80% lysis of pulmonary emboli ~80% of blood flow recovery in carotid artery	[30,31,32,36,38,39,103]
Thrombomodulin	Mouse	Acute Thrombosis Ischemic Stroke Endotoxemia	10% of drug present in blood 2 days post-injection vs. 1 h No changes in RBC survival	Complete protection against jugular vein thrombosis ~50% reduction in infarct volume and neurological deficit >50-fold improved potency at reduction of pro-inflammatory cytokines	[17,20]
Urokinase	Rabbit Mouse	Healthy Acute Thrombosis	Significant increase in blood exposure 14-fold increase in blood concentration at 30 min No changes in RBC survival	4–5-fold increase in blood flow following carotid artery thrombosis ~3-fold increase in blood flow following venous thrombosis	[33,40,104]

Notes: Unless otherwise noted, comparisons of PK/PD measurements are relative to free drug. Unless explicitly stated as being RBC related (e.g., RBC survival), all measurements relate to the PK of the therapeutic payload. Abbreviations used in table: AUC: area under the concentration vs. time curve, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, FEV1: forced expiratory volume, ADA: anti-drug antibody, Phe: phenylalanine.