Use and cardiovascular safety of transdermal and other granisetron preparations in cancer management

Figures & data

Table 1 Pharmacokinetics of granisetron

Health status	Age, years	Mean Cmax	Mean t1/2
IV granisetron*
Normal volunteers	21–42	64.3 ng/mL	4.91 hours
	65–81	57.0 ng/mL	7.69 hours
Patients with cancer		63.8 ng/mL	8.95 hours
Oral granisetron
Normal volunteers†		5.5 ng/mL	7.9 hours
Patients with cancer‡		5.9 ng/mL	–

Notes:

* 40 μg/kg;

† 2 mg qd;

‡ 1 mg bid.

Abbreviations: t_1/2, elimination half-life; IV, intravenous; qd, once a day; bid, twice a day; ng/mL, nanogram/milliliter; C_max, maximum plasma concentration.

Figure 1 Plasma concentrations of granisetron resulting from repeated oral dosing (2 mg daily) and the Sancuso 52 cm² TD patch¹⁷ in normal volunteers.

Note: The patch was removed at the end of day 6 (144 hours).

Abbreviations: TD, transdermal; ng/mL, nanogram/milliliter.

Figure 2 Plasma concentration in patients treated with the TD granisetron patch.

Note: Plasma concentration–time curve is very similar to that observed in normal subjects (Figure 1).

Abbreviations: TD, transdermal; ng/mL, nanogram/milliliter.

Table 2 IC₅₀ for hERG cardiac K⁺ channel inhibition

Drug	IC50 (μM)	IC50 reference	Mol wt	PB%	Oral dose	Cmax*	Safety margin
Palonosetron	6.50	European Medicines Agency^Citation22	296.4	62	0.25 mg	5.6	901
Dolasetron	5.95	Kuryshev^Citation30	324.4	73	100 mg	229.0	31
Granisetron	3.73	Kuryshev^Citation30	312.4	65	2 mg	5.5	605
Ondansetron	0.81	Kuryshev^Citation30	293.4	73	8 mg	38.1	35

Note:

* Mean at recommended oral dose, ng/mL.

Abbreviations: IC₅₀, concentration causing 50% inhibition of hERG tail current; hERG, human ether-a-go-go-related gene; K, potassium; Mol wt, molecular weight; PB%, percent protein bound; C_max, maximum plasma concentration.

Table 3 Incidence of most common adverse events

Adverse event	2 mg oral Kytril from label N = 1450	Oral granisetron development program N = 406	Patch granisetron development program N = 404
Headache	20%	4%	3%
Asthenia	18%	<3%	<3%
Dyspepsia	6%	<3%	<3%
Diarrhea	9%	4%	5%
Constipation	14%	5%	9%
Abdominal pain	4%	<3%	<3%

Modified with permission from Grossman J, Caspi A. Sancuso® Granisetron transdermal delivery system: a formulation for chemotherapy-induced nausea and vomiting. P&T Product Profiler. 2011(36);2:1–30.¹⁴

Table 4 Other 5-HT₃ antagonist preparations and other drug therapies for CINV in current use or under development

Drug	Class	Approval status	Comment
Ondansetron	5-HT3 antagonist	Approved; 32 mg IV dose withdrawn
Dolasetron	5-HT3 antagonist	Approved; IV withdrawn
Palonosetron	5-HT3 antagonist	Approved
Ramosetron	5-HT3 antagonist	Approved	Japan, SE Asia only
Tropisetron	5-HT3 antagonist	Approved	Not available in US
Granisetron SC	5-HT3 antagonist	Tested clinically; not approved	IV preparation; see Gurpide^Citation31
APF530	5-HT3 antagonist	Pending approval	Granisetron in polymer
Droperidol	Dopamine antagonist	Approved	Black box warning for ↑ QT
Dexamethasone	Corticosteroid	Approved	Adjunctive
Aprepitant	NK1 antagonist	Approved
Fosaprepitant	NK1 antagonist	Approved	Prodrug of aprepitant
Maropitant	NK1 antagonist	Veterinary use only
Vestipitant	NK1 antagonist	In development
Casopitant	NK1 antagonist	In development

Abbreviations: CINV, chemotherapy-induced nausea and vomiting; IV, intravenous; SC, subcutaneous; NK₁, neurokinin 1; ↑ QT, QT interval prolongation; SE, Southeast.

Figure 3 Linear regression of granisetron plasma concentration and associated placebo-corrected change in baseline-subtracted QTcF in the TQTS sponsored by ProStrakan, Inc.¹²

Notes: The slope of the relationship was 0.157 msec/9 ng/mL. The model predicted a ddQTcF at the maximum plasma concentration (26.1 ng/mL observed in the study of only 4.79 msec).

Abbreviations: QTcF, QT corrected by the Fridericia formula; TQTS, thorough QT study; ddQTcF, baseline and placebo subtracted QTcF; msec, millisecond; ng/ mL, nanogram/milliliter.

Figure 4 Linear regression the natural log of granisetron plasma concentration and associated placebo-corrected change in baseline-subtracted QTcF in the TQTS sponsored by AP Pharma Inc (2012).

Notes: The slope of the relationship was −0.1326 msec/9 ng/mL. The model predicted a ddQTcF at the maximum plasma concentration (82.1 ng/mL observed in the study of only 1.37 msec).

Abbreviations: QTcF, QT corrected by the Fridericia formula; ddQTcF, baseline and placebo subtracted QTcF; TQTS, thorough QT study; msec, millisecond; ng/ mL, nanogram/milliliter.

Table 5 Advantages and disadvantages of transdermal delivery of granisetron

Major advantages

Single application improves convenience and compliance

Presence/absence of patch improves compliance

Plasma concentration variability reduction avoids periodic toxicity and inefficacy

Minor advantages

Added alternative to other treatments

Discomfort of parenteral administration avoided

Major disadvantages

Must be applied 24 hours to 48 hours before chemotherapy

Loss of adhesion

Minor disadvantages

Skin irritation

Not applicable in acute treatment of CINV

Need to protect patch from water and perspiration

Abbreviation: CINV, chemotherapy-induced nausea and vomiting.

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