Review of the Mechanism of Action and Clinical Efficacy of Recombinant Human Hyaluronidase Coadministration with Current Prandial Insulin Formulations

Abstract

For patients with type 1 or type 2 diabetes, achieving good glycemic control is critical for successful treatment outcomes. As many patients remain unable to reach glycemic goals with currently available rapid-acting analog insulins, ultrafast insulin products are being developed that provide an even faster pharmacokinetic profile compared with current rapid prandial insulin products. The overall strategy of these ultrafast insulin products is to better mimic the normal physiologic response to insulin that occurs in healthy individuals to further improve glycemic control. Recombinant human hyaluronidase (rHuPH20) is a genetically engineered soluble hyaluronidase approved by the U.S. Food and Drug Administration as an adjuvant to increase the absorption and dispersion of other injected drugs; mammalian hyaluronidases as a class have over 6 decades of clinical use supporting the safety and/or efficacy of hyaluronidase coadministration. Clinical findings have demonstrated that coadministration of rHuPH20 with insulin or an insulin analog achieved faster systemic absorption, reduced inter- and intrapatient variability of insulin absorption, and achieved faster metabolic effects compared with injection of either insulin formulation alone. The magnitude of this acceleration is similar to the incrementally faster absorption of prandial insulin analogs as compared with regular insulin. In addition, coadministration of rHuPH20 with regular insulin or insulin analog also improved the achievement of prandial glycemic targets. Thus, rHuPH20 coadministration shows promise as a method of establishing a more rapid insulin profile to prandial insulin in patients with diabetes and has the potential to yield substantial improvements in postprandial glycemic excursion.

Introduction

The primary goal of insulin therapy is to restore glycemic control [i.e., derived average glucose (A1C) <7%¹ or <6.5%]^2,3 as close to normal as practicable by mimicking the time-action profile of physiologic insulin. Postprandial plasma glucose (PPG) is increasingly being recognized as an important factor in reaching this goal,³ especially as patients approach A1C target values. Indeed, postprandial hyperglycemia contributes the majority of total hyperglycemia for A1C values less than 8.5% and greater than 70% for A1C values less than 7.3%.^4,5 Targets for postprandial glucose control have been established by several professional organizations. The International Diabetes Federation and the American College of Endocrinology recommend that 2-hour postprandial values should be targeted below 140 mg/dl^2,3; the American Diabetes Association recommends that peak postprandial glucose be targeted below 180 mg/dl.¹ Current rapid prandial insulin products have faster insulin pharmacokinetics (PK) and insulin action than regular insulin following subcutaneous (SC) injection, especially for low-to-moderate doses (≤0.2 U/kg or ≤16 units; Table 1).^6,7 Despite this improvement, most patients are still unable to reach glycemic goals even with currently available rapid-acting analog insulins.¹⁵ Ultrafast insulin products are being developed that provide an even more rapid PK profile compared with current rapid prandial insulin products.^10,16,17 For example, an inhaled, dry powder insulin formulation has been developed that has a substantially faster time to peak plasma concentration (t_max) vs regular human insulin (12 to 17 minutes vs 2 hours postdose, respectively) and a more rapid return to baseline insulin concentrations (42 to 50 minutes) vs regular insulin (284 minutes).¹⁷ The overall strategy of these ultrafast insulin products is to better mimic the normal physiologic response to insulin that occurs in healthy individuals to provide important clinical benefits in the control of postprandial hyperglycemic excursions. Some of these ultrafast insulin formulations have demonstrated additional benefits, such as reduced weight gain and fewer hypoglycemic events, compared with regular human insulin¹⁸ or rapid-acting insulin analogs.^19–21

Table 1.

Euglycemic Glucose Clamp Study Results for Commercial Prandial Insulin Products

Reference	Dose	Insulin exposure (PK, min)			Insulin action (GIRa, min)
		Onset (early t50%)	Peak (tmax)	Offset (late t50%)	Onset (early t50%)	Peak (tmax)	Offset (late t50%)
Regular insulin
Rave et al 20058	18 U		148		48	193	415
Heinemann et al 19989	0.2 U/kg		129		61	156	387
Becker and Frick 20086	0.15 U/kg	53 (early t10%)	104	348 (late t90%)	88 (early t10%)	169	330 (late t90%)
Becker and Frick 20086	0.2 U/kg		82		43	161	306 (late t80%)
Heinemann et al 19989	0.2 U/kg		123			165
Lispro
Rave et al 20058	18 U		148		41	137	313
Vaughn et al 200910	20 U	40	98	231	72	193	324
Steiner et al 200811	12 U	26	66	170	51	152	295
Rave et al 200512	18 U		45		38	136	273
Rave et al 200512	12 U		45		38	112	248
Rave et al 200512	6 U		45		35	85	184
Heise et al 200713	0.2 U/kg	50 (early t10%)	76		87 (early t10%)	171
Heise et al 200713	0.4 U/kg	54 (early t10%)	92		88 (early t10%)	198
Becker and Frick 20086	0.2 U/kg		58		46	94	228 (late t80%)
Aspart
Heinemann et al 19989	0.2 U/kg		70		41	104	264
Mudaliar et al 199914	0.2 U/kg		52			94
Heinemann et al 19989	0.2 U/kg		48			104
Glulisine
Becker and Frick 20086	0.15 U/kg	31 (early t10%)	57	205 (late t90%)	45 (early t10%)	114	238 (late t90%)
Becker and Frick 20086	0.2 U/kg		51		34	98	218 (late t80%)
Becker and Frick 20086	0.1 U/kg		44		31	127
Heise et al 200713	0.2 U/kg	44 (early t10%)	94		83 (early t10%)	190
Heise et al 200713	0.4 U/kg	49 (early t10%)	100		85 (early t10%)	196

^aGIR, glucose infusion rate; t_50%, time to half-maximal plasma concentration.

Recombinant human hyaluronidase (rHuPH20) is approved by the U.S. Food and Drug Administration for administration as an adjuvant to increase the absorption and dispersion of other injected drugs.²² This genetically engineered enzyme lacks the C-terminal membrane-anchoring domain, rendering it soluble.²³ A proof-of-concept study in which healthy volunteers were administered rHuPH20 with or without regular human insulin or insulin analog demonstrated an acceleration of PK profiles for both insulin formulations.¹⁰ Coadministration of rHuPH20 increased the peak plasma concentration (C_max) by 90% for insulin lispro and 142% for regular insulin and reduced the t_max by 51% for insulin lispro and 58% for regular insulin. In addition, coadministration of rHuPH20 reduced the intersubject variability for various PK and glucodynamic measures.¹⁰ These faster PK results with rHuPH20 coadministration were confirmed and extended in two additional healthy volunteer studies^24–26 and during a meal study in patients with type 1 diabetes.²⁷ Results of the meal study demonstrated that the faster PK parameters reduced postmeal glycemic response without an increased risk of hypoglycemia.²⁷

The overall objectives of this review are to highlight the unmet needs even with the availability of current rapid-acting prandial products, to provide an overview of the history of hyaluronidase use and its mechanism of action in accelerating the absorption of coinjected drugs, and to review the emerging clinical pharmacology profile of prandial insulins coadministered with hyaluronidase.

Benefits and Limitations of Current Rapid-Acting Prandial Insulins

As summarized from a number of different studies, data shown in Table 2 demonstrate that rapid-acting insulin analogs reduce postprandial hyperglycemia relative to regular insulin injected at the same time.^16,28–33 These data also illustrate the impact of dose timing on glycemic response, such that in most cases, regular insulin administered approximately 30 to 60 minutes prior to a meal resulted in postprandial hyperglycemia comparable with rapid-acting analogs dosed 0 to 15 minutes before a meal.

Table 2.

Meal Challenge Study Results for Prandial Insulin Products^a

Study population	Test article	Dose	Meal content	Dose timing	PK tmax(min)	Glucose excursion (min*mg/dl)	Peak PPG (mg/dl)	Reference
T1DM	Regular	Not specifiedb	Three meals plus three snacks daily (kcal and CHO content not specified)	At meal	90	5,620	230	Wiefels et al. 199337
	Aspart			At meal	45	1,190	175
T1DM	Regular	0.15 U/kg	535 kcal (CHO contentnot specified)	At meal	98	23,600	295	Lindholm et al. 199933
	Regular			−30 min	80	19,900	261
	Aspart			At meal	40	16,000	243
T1DM	Regular	MeanDose 9 U (6–12)	543 kcal (55% CHO)	At meal	ND	19,300	254	Brunner et al. 200028
	Regular			−15 min	ND	14,700	239
	Aspart			At meal	ND	12,900	202
	Aspart			+15 min	ND	15,300	238
T1DM	Regular	0.15 U/kg	618 kcal (99 g CHO)	At meal	97	46,200	209	Rave et al. 200629
	Regular			−30 min	82	42,900	177
	Glulisine			At meal	55	42,500	180
	Glulisine			+15 min	57	46,600	208
T1DM	Regular	Meandose 6 U (2–18)	12 oz Ensure (60 g CHO)	At meal	116	9,620	190	Hompesch et al. 200927
	Lispro			At meal	49	6,520	174
	Lispro + PH20			At meal	30	4,430	148
T1DM	Regular	0.2 U/kg	“High” CHO	−30 to −45 min	ND	ND	250 (1 h)	Insulin lispro prescribing information30
	Lispro			−30 to −45 min	ND	ND	232 (1 h)
T1DM	Aspart or lispro	0.15 U/kg	Boost (80 g CHO)	At meal	78	15,700 (180 min)	74 (90 min)	Raz et al. 200916
	Aspart or lispro + heat			At meal	45	11,520 (180 min)	121 (90 min)
T2DM	Regular	0.15 U/kg	2000 kcal (85 g CHO)	At meal	90	19,800	216	Rosenfalck et al. 200031
	Regular			−30 min	82	15,600	200
	Aspart			At meal	62	16,200	194
T2DM	Regular	0.15 U/kg	633 kcal (83 g CHO)	−30 min	105	18,300	238	Perriello et al. 200532
	Aspart			At meal	70	14,600	225
TD2M	Inhaled insulin	198 U	ND	At meal	ND	ND	171 (1 h)	Gnudi et al. 200919
	Aspart	88 IU		At meal			209 (1 h)

^aCHO, carbohydrate; ND, not determined; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

^bStudy was performed with preparations of insulin formulations at a concentration of 100 U/ml. Patients were administered their individual basal rate of insulin formulation via pump delivery to reach a fasting blood glucose concentration below 7 mmol/liter (126 mg/dl).

However, these findings also demonstrate the limitations of current therapeutic offerings. Even with optimal dose timing in controlled laboratory settings, clinical targets for postprandial control are not met consistently. In the “real-world” setting, control of postprandial hyperglycemia is more challenging due to variations in dietary intake, insulin dose and timing, fear of hypoglycemia, and physical activity.³⁴ For example, it may be tempting for patients to dose prandial insulin immediately before meals to simplify lifestyle impacts of insulin treatment. Overall, clinical studies evaluating patient adherence to treatment and self-management of diabetes have consistently demonstrated the need for improvement, specifically with regard to self-monitoring, diet, and exercise.¹⁵

Enhanced Absorption through Hyaluronidase Coadministration

Mechanism of Action of Hyaluronidase

Hyaluronidase catalyzes the cleavage of the β1,4 linkage between N-acetylglucosamine and glucuronic acid residues of the hyaluronan long chain polymer,³⁵ and this breakdown of hyaluronan by hyaluronidase in the subcutaneous space results in enhanced permeation of coadministered agents.^22,36 The rHuPH20 acts as a permeation enhancer and rapidly increases the dispersion of coinjected molecules in a dose-dependent manner (Figure 1A).²³ Because rHuPH20 is rapidly metabolized locally without systemic exposure³⁶ and hyaluronan has a rapid turnover (i.e., one-third of the total body pool of 15 grams turns over daily),²³ the permeation effects of rHuPH20 and hyaluronidase are transient (i.e., reconstitutes within 6 to 25 hours; Figure 1B). Thus, both PH20 residence time and biochemical effects are transient and local, factors that suit it well for frequent and long-term use (as would be required for a prandial insulin product). Additionally, a favorable safety profile for rHuPH20 is supported by animal toxicology evaluations.³⁶

Figure 1.

Recombinant human hyaluronidase acts as a potent, reversible spreading factor in vivo. (A) Trypan blue dye in mice (50 μl) was coinjected locally with rHuPH20 (5.0, 0.5, or 0.005 units) or carrier control. (B) Recombinant human hyaluronidase (5 units) or United States Pharmacopeia hyaluronidase (5 units) was injected in the skin of mice followed by injection of trypan blue dye at the same site from 0.5 to 48 hours later. The effects of rHuPH20 were reversed by 24-hour postinjection. Reprinted with permission from Bookbinder and colleagues.²³

History of Hyaluronidase Administration

Over 60 years of clinical use support the safety and/or efficacy of hyaluronidase coadministration with a variety of injected drugs.^{10,23,38–42} The clinical safety and tolerability of hyaluronidase, which was first reported by Burket and Gyorgy in 1949,³⁸ have been established further with over 6 decades of use.^{10,23,39–42} Clinical history demonstrates the increased dispersion and faster absorption of a broad range of drugs and fluids administered with hyaluronidase products.^{10,23,38–44} With rHuPH20, for example, Thomas and colleagues^45,46 have demonstrated an accelerated PK profile of SC morphine coadministered with rHuPH20 compared with SC morphine alone, with earlier and greater peak exposure and comparable total bioavailability. Similarly, administration of rHuPH20 significantly enhanced gravity-driven SC infusion flow rates of fluid and electrolytes compared with placebo, leading the authors to suggest the possibility of using hyaluronidase-enabled SC infusions as replacements for pump-driven intravenous fluid therapy.⁴⁰

In keeping with the favorable safety profile of hyaluronidase as a class, rHuPH20 is well tolerated with a broad safety margin in a number of preclinical models.³⁶ Yocum and colleagues⁴⁷ assessed the sensitivity of healthy individuals to a single dose of rHuPH20 in a single-center, double-blind, placebo- and within-subject-controlled study. No allergic reactions (defined as occurrence of wheal with pseudopods within 5 minutes of injection that persisted for at least 20 minutes and was accompanied by localized itching) were observed among the 100 individuals who received a single intradermal injection of rHuPH20 (i.e., 0% allergic reaction rate).⁴⁷The incidence of any symptom of discomfort was significantly higher for saline compared with rHuPH20 (28% vs 3%, respectively; P< 0.0001), primarily because of stinging after saline injection (13%) compared with rHuPH20 (1%). The authors concluded that the higher incidence of discomfort related to injection of saline vs rHuPH20 was likely related to the rapid action of rHuPH20 as a spreading agent, effectively reducing the pressure required to inject the test agent. Taken together, observations of multiple studies highlight the potential uses and benefits of hyaluronidase administration in the clinical setting.

Effect of rHuPH20 on Insulin Absorption and Action

Mechanisms Underlying Absorption Kinetics of Subcutaneously Administered Insulin

Because most commercial drug formulations of insulin are predominately hexameric, insulin absorption is driven by the processes of both dissociation and diffusion.⁴⁸ Insulin hexamers are too large to be absorbed across capillary walls and must dissociate into dimers or monomers before absorption can occur.^48,49 Spontaneous dissociation of insulin occurs at low concentrations via equilibrium shift. In a traditional subcutaneous injection, insulin absorption is diffusion limited; insulin hexamers must first diffuse away from the site of injection to dissociate and become available for absorption.⁴¹ Thus, the absorption of insulin is affected by both insulin concentration and dose (Figure 2).⁴⁸ High concentrations and high doses are absorbed more slowly because of diffusion limitations.

Figure 2.

Diffusion-limited absorption is nonlinear such that higher insulin concentrations (A) and higher insulin doses (B) are absorbed more slowly. Reprinted with permission from Søeborg and colleagues.⁴⁸

Hyaluronidase acts as a spreading factor by rapidly digesting high-molecular weight hyaluronan, increasing bulk fluid flow away from the site of injection by about 20-fold.^17,30 Administration of rHuPH20 promotes rapid depolymerization of hyaluronan in the extracellular space to achieve rapid dilution of insulin to low concentrations that favor hexamer dissociation, which ultimately increases the rate of insulin absorption.^10,23 Thus, administration of rHuPH20 has the potential to reduce concentration-and dose-mediated limitations imposed on standard insulin formulations. The net effect is to accelerate the absorption of insulin with increased peak insulin exposure (C_max) without significantly affecting overall insulin exposure (total area under the curve).¹⁰ In addition to the promotion of hexamer dissociation, rHuPH20 accelerates absorption by the general hyaluronidase mechanism of dispersing the drug over a larger capillary bed, which improves absorption flux.²³

Clinical Pharmacology Studies

A phase 1, glucose-clamp study compared the insulin time-concentration profile (PK) and glucodynamics of insulin lispro and regular human insulin administered with or without rHuPH20 to healthy volunteers (Table 3).¹⁰ Coadministration of rHuPH20 substantially increased the rate and peak level (C_max) of absorption of both insulin formulations compared with either agent alone. Although requiring a comparison across cohorts, coadministration with rHuPH20 appeared to produce an acceleration of a magnitude comparable to the faster absorption of the rapid insulin analog relative to regular insulin. Similarly, rHuPH20 coadministration resulted in accelerated glucose metabolism compared with either formulation alone. The acceleration of insulin absorption and insulin action has been confirmed and extended in two subsequent healthy volunteer studies.^24–26

Table 3.

Pharmacokinetics and Glucose Infusion Rate Parameters for Prandial SC Insulin Products under Development

Reference	Dose	Insulin exposure			Insulin action
		Onset (early t50%)	Peak (tmax)	Offset (late t50%)	Onset (early t50%)	Peak (tmax)	Offset (late t50%)
Regular insulin
	≤16 U (0.2 U/kg)	∼45 min	∼2 h	4–5 h	∼1 h	∼2.5 h	∼6 h
Vaughn et al. 200910	20 U	47 min	163 min	279 min	104 min	253 min	>360 min
Steiner et al. 200818	12 U	37 min	120 min	260 min	66 min	193 min	357 min
Rapid-acting analogs
	≤16 U (0.2 U/kg)	∼30 min	45–60 min	∼3 h	30–40 min	∼2 h	∼4 h
	>20 U	∼45 min	1.5 h	∼4 h	75–90 min	∼3 h	5–6 h
Vaughn et al. 200910	20 U	40 min	98 min	231 min	72 min	193 min	324 min
Halozyme50	0.15 U/kg	25 min	55 min	144 min	61 min	99 min	157 min
Steiner et al. 200818	12 U	26 min	66 min	170 min	51 min	152 min	295 min
Lispro + PH20
Vaughn et al. 200910	20 U	26 min (66%)a	48 min (49%)	110 min (48%)	44 min (61%)	114 min (59%)	275 min (85%)
Halozyme50	0.15 U/kg	14 min (57%)	40 min (72%)	88 min (61%)	43 min (70%)	72 min (73%)	119 min (76%)
Viaject
Steiner et al. 200818	12 U	18 min (69%)	60 min (91%)	181 min (107%)	33 min (65%)	136 min (89%)	280 min (95%)
Steiner et al. 200818	6 U	7 min	51 min	145 min	35 min	115 min	270 min
Steiner et al. 200818	3 U	12 min	54 min	126 min	31 min	111 min	297 min
Inhaled insulin
	25 U		12 min	45 min		42 min
Rave et al. 200917	50 U	NDb	15 min	42 min	ND	50 min	ND
	100 U		17 min	50 min		58 min

^aValues in parentheses represent percentage of control.

^bNot determined.

In the original healthy volunteer study, it also was observed that rHuPH20 greatly reduced the intersubject variability of important PK and glucodynamic parameters, which suggested the possibility that hyaluronidase coinjection may also reduce intrasubject variability.¹⁰ To test this hypothesis, a second healthy volunteer study was conducted in 20 subjects, each receiving two doses each of three study drugs: insulin + PH20, lispro + PH20, or lispro alone. Coadministration with rHuPH20 significantly reduced the intrasubject variability of early insulin exposure and the timing of insulin absorption.²⁶

The dose-normalized PK responses to regular insulin and insulin lispro with and without rHuPH20 were compared in separate studies of healthy volunteers and patients with type 1 diabetes (Figure 3). The high doses of insulin lispro (without rHuPH20) administered in the healthy volunteer study resulted in a lower dose-normalized C_max than that observed with the lower doses of insulin administered in the meal study in patients with type 1 diabetes. However, when rHuPH20 was administered with insulin lispro in these studies, the dose-normalized C_max values were comparable, suggesting that coadministration of rHuPH20 may attenuate this dose-dependent nonproportionality in PK responses. This effect was further studied in a third healthy volunteer study conducted over multiple dose cohorts. The first two stages were used to examine the dose–response effect of increasing rHuPH20 concentrations on the absorption of regular insulin and insulin lispro, which was found to be accelerated over a wide concentration range (0.3 to 80 μg/ml), with an optimum effect at or about 5 μg/ml.²⁴ The second two stages demonstrated that a fixed ratio of rHuPH20 to insulin (5 μg rHuPH20/100 units insulin) accelerated insulin absorption and action over clinically relevant doses of insulin lispro (2 to 20 units) and regular insulin (6 to 24 units). Over these ranges, greater insulin doses showed slower rates of early insulin absorption, and this effect was generally reduced (but not eliminated) with rHuPH20 coadministration.²⁵

Figure 3.

Coadministration of rHuPH20 with insulin lispro suppressed nonlinearity of insulin PK with insulin dose in separate studies of healthy volunteers (each receiving a 20-unit dose) and patients with type 1 diabetes (each receiving individualized dose); y axis values normalized to per unit of insulin administered.

To examine how the accelerated insulin absorption impacts control of postprandial glucose excursions, a phase 2, within-patient, single-blind, crossover standardized test meal study was conducted in patients with type 1 diabetes (N = 21).²⁷ Insulin PK and glucose response to a liquid meal was measured after injection of regular human insulin or insulin lispro with or without coadministration of rHuPH20. As observed previously in healthy volunteers, coadministration of rHuPH20 accelerated the absorption of regular insulin and insulin lispro in patients with type 1 diabetes (Figure 4). Coadministration of rHuPH20 with insulin lispro or regular insulin also improved the achievement of glycemic targets, such that mean peak PPG levels were reduced from 190 to 166 mg/dl with regular insulin (P = 0.017) and from 174 to 148 mg/dl with insulin lispro (P = 0.002). Thus, the 24- to 26-mg/ml reduction in peak PPG levels for coadministration of either insulin with rHuPH20 was meaningful relative to the 16-mg/dl reduction in peak PPG with lispro compared with regular insulin. Postprandial hypoglycemic excursions were generally mild and overall hypoglycemic risk was comparable for insulin lispro with or without rHuPH20, and coadministration of regular insulin with rHuPH20 reduced postprandial hypoglycemia risk compared with regular insulin alone. Based on these findings, the authors concluded that a coformulation of insulin with rHuPH20 may benefit patients with diabetes by decreasing postmeal hyperglycemic excursions without increasing the risk for hypoglycemia.

Figure 4.

Pharmacodynamic findings of meal time study in patients with type 1 diabetes demonstrated that coadministration of rHuPH20 improved achievement of glycemic targets.²⁷

The addition of rHuPH20 to insulin lispro and regular insulin has been well tolerated and no severe or serious adverse events were observed in any of these four clinical studies. Additional clinical studies also have reported the overall safety and tolerability of rHuPH20 coadministration with other agents.^40–42 It should be noted that there is no long-term, repeat dose exposure to rHuPH20 data available; an ongoing 3-month × 3-month crossover study comparing regular insulin–PH20 to insulin lispro in 48 type 1 diabetic subjects did not uncover any safety or tolerability signals at the time of an interim safety analysis among the 22 subjects receiving regular insulin–PH20 (data not shown); longer term data in larger numbers of subjects will be needed to better address this question.

Conclusions

Coadministration of rHuPH20 with insulin or an insulin analog was well tolerated and accelerated insulin absorption by a magnitude similar to the accelerated absorption of rapid analogs relative to regular insulin. Recombinant human hyaluronidase reduced the variability of intrasubject and intersubject insulin PK and reduced the delay in absorption seen for higher doses of insulin. This genetically engineered soluble hyaluronidase shows promise as a method of establishing a more rapid insulin profile to prandial insulin, which leads to more physiologically appropriate responses to prandial nutrient challenge. This more rapid insulin absorption resulted in improved control of postprandial glucose excursions in a liquid meal challenge. Control of postprandial plasma glucose levels is critical to achieving target glycemic goals and providing successful treatment outcomes for patients with diabetes.^4,5 In this regard, coadministration of rHuPH20 has the potential to result in substantial improvements in postprandial glycemic control.

Abbreviations

A1C

derived average glucose

C_max

peak plasma concentration

PK

pharmacokinetics

PPG

postprandial plasma glucose

rHuPH20

recombinant human hyaluronidase

SC

subcutaneous

t_max

time to peak plasma concentration