- Email: [email protected]
The evaluation of drug rechallenge: The casopitant Phase III program
Regulatory Toxicology and Pharmacology 58 (2010) 539–543
Contents lists available at ScienceDirect
Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph
The evaluation of drug rechallenge: The casopitant Phase III program Christine M. Hunt a,⇑, Julie I. Papay a, Donna S. Rich b, Christopher J. Abissi b, Mark W. Russo b a b
GlaxoSmithKline, RTP, Durham, NC 27709, USA GlaxoSmithKline, Collegeville, PA 19426, USA
a r t i c l e
i n f o
Article history: Received 29 June 2010 Available online 13 October 2010 Keywords: Rechallenge Drug-induced liver injury Hepatotoxicity Mitochondrial dysfunction Immunoallergic injury Liver injury Liver safety Clinical trial Casopitant
a b s t r a c t Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, is associated with 13% mortality in prospective series. Rechallenge generally results in much more rapid injury than the initial liver event. The neurokinin-1 antagonist casopitant or its placebo was administered cyclically with ondansetron and dexamethasone in two randomized chemotherapy-induced nausea and vomiting clinical trials in nearly 3000 subjects. Grade 3 ALT elevations were observed in up to 2% of subjects receiving casopitant or placebo treatment. Similar rates of positive rechallenge were observed in the casopitant 8/ 29 (28%) and placebo groups 2/8 (25%), with no Grade 4 ALT elevations, hypersensitivity or liver-related serious adverse events. Publishing available rechallenge data (positive and negative) will advance our clinical understanding. Rechallenge should only be considered when the potential drug benefit exceeds the risk. Ó 2010 Elsevier Inc. All rights reserved.
1. Introduction Drug rechallenge following an event of drug-induced liver injury results in up to 13% mortality in prospective studies (Andrade et al., 2005) and 2–51% mortality in retrospective studies (Papay et al., 2009; Mushin et al., 1971). However, risk factors for severe liver injury remain poorly characterized (Mushin et al., 1971; Andrade et al., 2005, 2009a,b; Papay et al., 2009) and clinical outcomes following drug rechallenge appear to vary markedly by drug (Watkins et al., 1994; Papay et al., 2009). When assessing drug-induced liver injury in global causality assessment scales, rechallenge is one of the weightiest measures (Tajiri and Shimizu, 2008). However, published data on drug rechallenge remains sparse, and additional data are sought to inform clinical decision making. While drug rechallenge is typically avoided, it may occur in certain treatment settings, and sometimes inadvertently, such as when a drug is administered cyclically (e.g. chemotherapy). When a dose-limiting toxicity arises in oncology clinical studies (National Cancer Institute website), treatment is commonly interrupted and restarted when toxicity resolves. Hence, treatment interruptions due to liver chemistry elevations may be followed by treatment reinitiation, which constitutes a drug rechallenge. The large number of potentially toxic agents used to treat these subjects intro⇑ Corresponding author. Address: GlaxoSmithKline, 5 Moore Drive, RTP, NC 27709, USA. Fax: +1 919 315 0495. E-mail addresses: [email protected], [email protected] (C.M. Hunt). 0273-2300/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2010.09.014
duces complexity in the interpretation of the causal relationship of the initial event as well as in making predictions of subsequent events. Without clear information conveyed linking a drug and an event of liver injury, patients may self-medicate, and hence rechallenge, with the culpable drug (Papay et al., 2009; Andrade et al., 2009a,b). Drug rechallenge may also result from sporadic noncompliance. Casopitant (an NK-1 antagonist piperidine derivative) was studied in two Phase III chemotherapy-induced nausea and vomiting clinical studies (Herrstedt et al., 2009; Grunberg et al., 2009) representing 1978 casopitant treated subjects, and 744 placebo treated subjects. All received other antiemetic agents (ondansetron and dexamethasone) as well as cytotoxic chemotherapy for their cancer. Casopitant is metabolized primarily by CYP3A4 and to a lesser extent, CYP2D6. It also exhibits mild to moderate CYP3A4 inhibition. Casopitant or its metabolites accumulate in tissues with chronic dosing, which may contribute to the chemistry elevations and/or histopathologic changes observed in several organs (liver, heart, and kidney) of chronically treated rats and dogs at cumulative casopitant exposures far exceeding those observed with clinical use. In addition, mitochondrial function following casopitant exposure was examined ex vivo, revealing only inhibition of Ca2+induced swelling in canine cardiac mitochondria. Control anti-emetics with or without casopitant were administered cyclically with moderately (Herrstedt et al., 2009) and highly emetogenic chemotherapies (Grunberg et al., 2009). Similarly in both placebo and casopitant treatment groups, Grade 2 liver chemistry elevations were observed in 3–9% and Grade 3 elevations
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C.M. Hunt et al. / Regulatory Toxicology and Pharmacology 58 (2010) 539–543
in 0–2% of subjects. One or more drug rechallenges occurred as subjects received additional chemotherapy cycles along with recurrent casopitant or placebo treatment upon return to Grade 1 liver chemistries. The effect of these drug rechallenges on liver chemistry elevations and clinical outcomes was examined in these studies and is compared with published drug-specific rechallenge information. 2. Methods Patient populations and methods for these two randomized, double-blind, placebo-controlled, multi-national studies have been reported (Grunberg et al., 2009; Herrstedt et al., 2009). In brief, patients were required to have evidence of adequate organ function, including bilirubin 6 1.5 upper limit of normal [ULN], AST and ALT 6 2.5 ULN, or AST and ALT 6 5.0 ULN in the presence of known liver metastases. Adult chemotherapy-naïve patients were enrolled and received dexamethasone 8 mg IV on day 1 and ondansetron 8 mg orally twice daily on days 1–3 of either moderately or highly emetogenic chemotherapy. Patients were then randomly assigned to also receive placebo, single 150 mg oral dose of casopitant mesylate, 3-day intravenous plus oral casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3) or casopitant 3-day oral dosage (150 mg PO on day 1 and 50 mg PO on days 2 and 3). The primary endpoint was the proportion of patients achieving complete response (no vomiting, retching, or use of rescue medications) in the first 120 h of the first cycle of emetogenic chemotherapy. Subjects were allowed to continue study treatment if they continued to meet eligibility requirements. Laboratory tests and adverse events were reported and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 for the safety population (with Grade 1, ALT > ULN to 2.5 ULN; Grade 2, ALT > 2.5–5 ULN; Grade 3, ALT > 5–20 ULN; Grade 4, ALT > 20 ULN; Grade 5, death). All subjects who received any investigational product constituted the safety population for the safety analyses. Liver chemistries were obtained pretreatment during screening, treatment days 6–10, and at completion of each cycle. Liver injury events were categorized by type of liver injury as hepatocellular, mixed or cholestatic (Danan and Benichou, 1993). Subjects with ALT elevations greater than or equal to 3 times upper limit of normal (ULN) were identified for the analysis. Cases were then excluded if there was no subsequent dosing following the ALT elevation or if the initial reported ALT elevation never recovered or failed to decrease prior to subsequent dosing. A ‘‘positive” rechallenge was defined as an elevation of ALT P 3 ULN during the treatment phase, with a recovery (or decrease) of P50%, that was followed by a recurrent elevation of ALT P 2 ULN following subsequent administration of investigational product (Danan and Benichou, 1993), and was temporally associated with dosing. A ‘‘negative” rechallenge was defined as an elevation of ALT P 3 ULN during the treatment phase that was not associated with a recurrent elevation (ALT P 2 ULN) following subsequent additional dosing of investigational product (Danan and Benichou, 1993). Published positive rechallenge cases were assessed with respect to liver injury type, timing of drug administration with respect to liver injury and results of positive rechallenge as previously defined (Benichou et al., 1993). 3. Results 3.1. Casopitant Phase III clinical trials In the Phase III study of moderately emetogenic chemotherapy, NKV102549, 1933 predominantly female subjects (98%), of median
age 52, diagnosed with breast cancer (96%) and scheduled to receive an anthracycline and cyclophosphamide-based chemotherapy were enrolled and randomized 1:1:1:1 to placebo (n = 483), casopitant single oral dose (n = 483), casopitant 3 day oral dose (n = 483), or casopitant 3 day intravenous/oral dose (n = 484) treatments (Herrstedt et al., 2009). All subjects who received any investigational product constituted the safety population (n = 1890) for the safety analyses. In the Phase III study of highly emetogenic chemotherapy, NKV102551, 810 predominantly male subjects (67–69%), of median age 58, diagnosed with a variety of solid tumors (with nonsmall cell lung cancer in >50%), and predominantly cisplatin-based (98–99%) chemotherapy were enrolled and randomly assigned 1:1:1 to receive placebo (n = 269), casopitant single oral dose (n = 271), or casopitant 3 day intravenous/oral dose (n = 270) treatments (Grunberg et al., 2009). The safety analysis included all subjects in the safety population (n = 788). Liver chemistries were generally similar across treatment groups in both studies, with 2% or fewer Grade 3 ALT elevations in any treatment group (Table 1). Of more than 2500 subjects, only three subjects exhibited ALT P 3 ULN with concomitant bilirubin P 2 ULN; all were in the highly emetogenic chemotherapy study (where two received placebo and the remaining subject with progressive biliary carcinoma received a single oral dose of casopitant). Across both studies, ALT P 3 ULN was observed in 91 subjects receiving casopitant or placebo and anti-cancer chemotherapy. Of these 91 subjects, 53 subjects did not have subsequent dosing following the ALT elevation and one subject had no recovery from the ALT elevation between dosing. These subjects were therefore excluded from the rechallenge analysis. The remaining 37 subjects met rechallenge criteria: 10 exhibited positive rechallenge (i.e., with a recurrent ALT elevation post-redosing), and 27 subjects had a negative rechallenge (i.e., no recurrent ALT elevation with subsequent dosing). A positive rechallenge was observed in similar proportions in the casopitant and placebo groups: 28% (8 of 29) in the casopitant treatment groups overall, compared with 25% (2 of 8) in the placebo group (also receiving ondansetron and dexamethasone) (Table 2). In the placebo group, peak ALT with rechallenge was less than 3 ULN. In all subjects with positive rechallenge in the casopitant treatment groups, peak ALT was less than 10 ULN for the primary and rechallenge events (Fig. 1 provides representative graphs). No liver-related serious adverse events or hypersensitivity reactions associated with the positive rechallenge were reported in any treatment group. 3.2. Rechallenge events with marketed drugs In prospective and retrospective drug rechallenge series (Andrade et al., 2009a,b; Papay et al., 2009), hepatocellular injury and jaundice were most common, antibiotics were the most frequent suspect medication, and most drug rechallenges were inadvertent. When compared to the initial liver injury, rechallenge was generally associated with a shorter time interval to recurrent liver injury. Many drugs associated with serious positive or fatal rechallenge are associated with mitochondrial impairment, hypersensitivity or immunoallergic injury and reactive metabolites. 4. Discussion Cyclic administration of casopitant or placebo (with concomitant ondansetron and dexamethasone) in two Phase III studies of chemotherapy-induced nausea and vomiting was associated with ALT > 5 ULN in up to 2% of subjects. In the absence of casopitant, ondansetron is generally associated with mild, transient, asymptomatic transaminase elevations > 2 ULN, which may recur
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C.M. Hunt et al. / Regulatory Toxicology and Pharmacology 58 (2010) 539–543 Table 1 Summary of maximum ALT in all cycles (safety populationa). Dose group
n
ALT – NKV102549 moderately Control Single dose oral 3-Day oral 3-Day IV/oral
Grade 0, n (%)
emetogenic chemotherapy 471 316 (67) 474 324 (68) 474 296 (62) 471 307 (65)
ALT – NKV102551 highly emetogenic chemotherapy Control 261 161 (62) Single dose oral 263 151 (57) 3-Day IV/oral 264 160 (61)
Grade 2, n (%)
Grade 3, n (%)
Grade 4, n (%)
134 122 157 137
21 26 16 19
(4) (5) (3) (4)
0 2 (<1) 5 (1) 7 (1)
0 0 0 1 (<1)
10 (4) 17 (6) 23 (9)
5 (2) 3 (1) 1 (<1)
0 0 0
(28) (28) (33) (29)
85 (33) 92 (35) 80 (30)
Safety population subjects with liver chemistry data.
Treatment groups Control, n
Study NKV102551, n = 15 Positive rechallenge Negative rechallenge Study NKV102549, n = 22 Positive rechallenge Negative rechallenge
2 2
Single dose oral, n
3-Day oral, n
0 2
3-Day IV/ oral, n 6 3
10 9
Exposure ALT(SGPT) AST(SGOT) TOTAL BILIRUBIN
8 7 6 5 4 3 2 1 0
0 4
0 7
2 3
0 6
Combined analyses, n = 37 Positive rechallenge 2 Negative rechallenge 6 % Positive rechallenge 25
0 9 0
2 3 40
6 9 40
with readministration in some subjects receiving cyclophosphamide-based chemotherapy (DailyMed); hypersensitivity with ondansetron rechallenge has been reported (Papay et al., 2009). In the casopitant Phase III studies, 91 subjects received investigational agent (casopitant or placebo) and experienced ALT P 3 ULN. Of these 91 subjects, only 10 subjects across all groups met positive rechallenge criteria. Similar numbers (25–28%) of positive drug rechallenge liver events were observed in the casopitant and placebo groups and none were accompanied by hypersensitivity symptoms or hospitalization. So, positive rechallenge was generally well tolerated in all subjects. In some subjects, a pattern consistent with adaptation or tolerance on positive rechallenge was observed (as portrayed in Fig. 1). These clinically unremarkable casopitant rechallenge data are presented to enhance the understanding of drug rechallenge events following potential drug-induced liver injury in controlled clinical trials. Very few controlled studies of drug rechallenge have been published; most published data arises from inadvertent rechallenge reported in case series highlighting severe or fatal events (suggesting a likely publication bias). So, while the casopitant rechallenge data provides quite limited case numbers and exclusively asymptomatic transaminase elevations, it provides useful controlled comparative data to augment the rechallenge evidence base. In contrast to published rechallenge data on marketed drugs, casopitant rechallenge was not associated with serious liver injury or fatality, hypersensitivity or immunoallergic injury, or significant mitochondrial impairment. Typically, fewer than 1 in 1000 exposed patients develop severe drug-induced liver injury (Kaplowitz, 2005), suggesting a heightened vulnerability in those affected, which may be due to a concurrent, potentially transient, inflammation (Roth et al., 2003; Cosgrove et al., 2009) and resultant oxidative stress, concomitant medications contributing to defective regeneration/repair (Suzuki et al., 2009), high drug dose or hepatic metabolism (Lammert
-25
0
25
50
75
100
50
75
100
50
75
100
StudyDay
b Liver Ch he emisttrie es (/U UL LN))
Rechallenge response
a Liver Ch he emisttrie es (/U UL LN))
Table 2 Summary of rechallenge assessments (safety population) for Phase III studies: NKV102551 (highly emetogenic chemotherapy study) and NKV102549 (moderately emetogenic chemotherapy study).
10 9
Exposure ALKALINE PHOSPHATASE ALT (SGPT) AST (SGOT) TOTAL BILIRUBIN
8 7 6 5 4 3 2 1 0
-25
0
25
StudyDay
c Liv ver Ch C em mis strries (/U ( ULN N)
a
Grade 1, n (%)
10 9 8 7 6 5 4 3 2 1 0
Exposure ALKALINE PHOSPHATASE ALT (SGPT) AST (SGOT) TOTAL `BILIRUBIN
-25
0
25
Study Day Fig. 1. (a–c) Liver chemistry elevations are profiled in three subjects receiving repeated exposures (or rechallenges) of casopitant with concomitant ondansetron, dexamethasone and emetogenic chemotherapy over time. (c) (last slide) Profiles a subject with evidence of adaptation or tolerance, with diminishing ALT elevations on repeated rechallenge.
et al., 2010), female gender or obesity (Podevin and Biour, 1995), genetic susceptibility (Andrade et al., 2009a,b), or other factors. Mitochondrial impairment (Hanley et al., 2002; Mansouri et al., 2003; Tapner et al., 2004; Ohlson et al., 2004) and immunoallergic injury (e.g. drug-specific HLA associated with hepatotoxicity, signs or symptoms of hypersensitivity, or drug-associated antibodies) (Podevin and Biour, 1995) were frequently reported among drugs with positive or fatal rechallenge and likely increase the risk of rechallenge. In particular, cumulative mitochondrial impairment
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likely increases the risk of positive rechallenge, resulting in more rapid rechallenge injury (Jones et al., 2010). Fatal halothane rechallenge events are widely attributed to immune-mediated liver injury due to the rapidity of injury with rechallenge (particularly with rechallenge within 4 weeks of primary injury) and associated fever, eosinophilia, and anti-liverkidney-microsomal (anti-LKM-1) and adduct antibodies (Uetrecht, 2008; Podevin and Biour, 1995). Halothane-associated mitochondrial inhibition is also reported (Hanley et al., 2002; Ohlson et al., 2004). Immunoallergic injury and cross-sensitization have been reported for anticonvulsants (Shear and Spielberg, 1988) and antidepressants (DeSanty and Amabile, 2007). HLA markers highly associated with liver injury have recently been reported for antibiotics and drugs of diverse classes (Nelson, 2010; Spraggs, 2010; Daly et al., 2009; Kindmark et al., 2008; O’Donohue et al., 2000). In clinical development, drug rechallenge most frequently arises in oncology trials, where drug is typically withheld when Grade 3–4 toxicity arises yet there’s evidence of benefit resulting in interest in readminstration/rechallenge when the toxicity resolves. While published data is limited and likely biased to more severe clinical outcomes, the presence of concomitant mitochondrial impairment and immunoallergic injury appear most associated with fatal or positive rechallenge, while the absence of these factors may suggest a more favorable rechallenge outcome. The cumulative effects of other risk factors such as oxidative stress, reactive metabolites, intraindividual or environmental factors, effects of infection/inflammation or comedications on drug rechallenge events remain incompletely characterized. More data is needed to examine these factors which could be obtained through publication of ‘‘inadvertent” rechallenge data from clinical trials (e.g. of drugs with cyclic adminstration) or global drug-induced liver injury registries. Such an expanded evidence base could identify additional targeted risk factors to predict clinically important positive rechallenge events, which could be instrumental in assessing possible rechallenge of critical medicines. 5. Conclusions Analysis of controlled clinical trial events reveals positive rechallenge occurring at a similar rate in those receiving casopitant or placebo in two Phase III studies, with no serious clinical outcomes or Grade 4 ALT elevations. In contrast, review of published case series suggest that drugs causing mitochondrial, immunoallergic and hepatocellular injury are associated with a higher rate of clinically important and even fatal positive rechallenge reactions. Cumulative mitochondrial dysfunction may particularly increase the risk of positive rechallenge when a suspect drug is restarted within weeks of the primary injury. So, drug rechallenge should generally be avoided and considered only if the benefit exceeds the risk (e.g. life-saving drug). Publication of drug-specific rechallenge information from controlled clinical trials and liver injury registries will further elucidate risk factors for positive rechallenge. Understanding risk factors and mechanisms of primary and rechallenge liver injury, as well as clinical outcomes, through an expanded evidence base, will advance drug safety. Conflict of interest statement All authors are fully employed by GSK. Acknowledgments The authors wish to thank the Casopitant Project Team, Steve Lane, Jon Lyon, and the GSK Hepatotoxicity Board for their expert input and Cynthia Traynham for her administrative assistance.
The corresponding author affirms that she has listed everyone who contributed significantly to the work.
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Contents lists available at ScienceDirect
Regulatory Toxicology and Pharmacology journal homepage: www.elsevier.com/locate/yrtph
The evaluation of drug rechallenge: The casopitant Phase III program Christine M. Hunt a,⇑, Julie I. Papay a, Donna S. Rich b, Christopher J. Abissi b, Mark W. Russo b a b
GlaxoSmithKline, RTP, Durham, NC 27709, USA GlaxoSmithKline, Collegeville, PA 19426, USA
a r t i c l e
i n f o
Article history: Received 29 June 2010 Available online 13 October 2010 Keywords: Rechallenge Drug-induced liver injury Hepatotoxicity Mitochondrial dysfunction Immunoallergic injury Liver injury Liver safety Clinical trial Casopitant
a b s t r a c t Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, is associated with 13% mortality in prospective series. Rechallenge generally results in much more rapid injury than the initial liver event. The neurokinin-1 antagonist casopitant or its placebo was administered cyclically with ondansetron and dexamethasone in two randomized chemotherapy-induced nausea and vomiting clinical trials in nearly 3000 subjects. Grade 3 ALT elevations were observed in up to 2% of subjects receiving casopitant or placebo treatment. Similar rates of positive rechallenge were observed in the casopitant 8/ 29 (28%) and placebo groups 2/8 (25%), with no Grade 4 ALT elevations, hypersensitivity or liver-related serious adverse events. Publishing available rechallenge data (positive and negative) will advance our clinical understanding. Rechallenge should only be considered when the potential drug benefit exceeds the risk. Ó 2010 Elsevier Inc. All rights reserved.
1. Introduction Drug rechallenge following an event of drug-induced liver injury results in up to 13% mortality in prospective studies (Andrade et al., 2005) and 2–51% mortality in retrospective studies (Papay et al., 2009; Mushin et al., 1971). However, risk factors for severe liver injury remain poorly characterized (Mushin et al., 1971; Andrade et al., 2005, 2009a,b; Papay et al., 2009) and clinical outcomes following drug rechallenge appear to vary markedly by drug (Watkins et al., 1994; Papay et al., 2009). When assessing drug-induced liver injury in global causality assessment scales, rechallenge is one of the weightiest measures (Tajiri and Shimizu, 2008). However, published data on drug rechallenge remains sparse, and additional data are sought to inform clinical decision making. While drug rechallenge is typically avoided, it may occur in certain treatment settings, and sometimes inadvertently, such as when a drug is administered cyclically (e.g. chemotherapy). When a dose-limiting toxicity arises in oncology clinical studies (National Cancer Institute website), treatment is commonly interrupted and restarted when toxicity resolves. Hence, treatment interruptions due to liver chemistry elevations may be followed by treatment reinitiation, which constitutes a drug rechallenge. The large number of potentially toxic agents used to treat these subjects intro⇑ Corresponding author. Address: GlaxoSmithKline, 5 Moore Drive, RTP, NC 27709, USA. Fax: +1 919 315 0495. E-mail addresses: [email protected], [email protected] (C.M. Hunt). 0273-2300/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.yrtph.2010.09.014
duces complexity in the interpretation of the causal relationship of the initial event as well as in making predictions of subsequent events. Without clear information conveyed linking a drug and an event of liver injury, patients may self-medicate, and hence rechallenge, with the culpable drug (Papay et al., 2009; Andrade et al., 2009a,b). Drug rechallenge may also result from sporadic noncompliance. Casopitant (an NK-1 antagonist piperidine derivative) was studied in two Phase III chemotherapy-induced nausea and vomiting clinical studies (Herrstedt et al., 2009; Grunberg et al., 2009) representing 1978 casopitant treated subjects, and 744 placebo treated subjects. All received other antiemetic agents (ondansetron and dexamethasone) as well as cytotoxic chemotherapy for their cancer. Casopitant is metabolized primarily by CYP3A4 and to a lesser extent, CYP2D6. It also exhibits mild to moderate CYP3A4 inhibition. Casopitant or its metabolites accumulate in tissues with chronic dosing, which may contribute to the chemistry elevations and/or histopathologic changes observed in several organs (liver, heart, and kidney) of chronically treated rats and dogs at cumulative casopitant exposures far exceeding those observed with clinical use. In addition, mitochondrial function following casopitant exposure was examined ex vivo, revealing only inhibition of Ca2+induced swelling in canine cardiac mitochondria. Control anti-emetics with or without casopitant were administered cyclically with moderately (Herrstedt et al., 2009) and highly emetogenic chemotherapies (Grunberg et al., 2009). Similarly in both placebo and casopitant treatment groups, Grade 2 liver chemistry elevations were observed in 3–9% and Grade 3 elevations
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C.M. Hunt et al. / Regulatory Toxicology and Pharmacology 58 (2010) 539–543
in 0–2% of subjects. One or more drug rechallenges occurred as subjects received additional chemotherapy cycles along with recurrent casopitant or placebo treatment upon return to Grade 1 liver chemistries. The effect of these drug rechallenges on liver chemistry elevations and clinical outcomes was examined in these studies and is compared with published drug-specific rechallenge information. 2. Methods Patient populations and methods for these two randomized, double-blind, placebo-controlled, multi-national studies have been reported (Grunberg et al., 2009; Herrstedt et al., 2009). In brief, patients were required to have evidence of adequate organ function, including bilirubin 6 1.5 upper limit of normal [ULN], AST and ALT 6 2.5 ULN, or AST and ALT 6 5.0 ULN in the presence of known liver metastases. Adult chemotherapy-naïve patients were enrolled and received dexamethasone 8 mg IV on day 1 and ondansetron 8 mg orally twice daily on days 1–3 of either moderately or highly emetogenic chemotherapy. Patients were then randomly assigned to also receive placebo, single 150 mg oral dose of casopitant mesylate, 3-day intravenous plus oral casopitant mesylate (90 mg intravenous on day 1 plus 50 mg oral on days 2 and 3) or casopitant 3-day oral dosage (150 mg PO on day 1 and 50 mg PO on days 2 and 3). The primary endpoint was the proportion of patients achieving complete response (no vomiting, retching, or use of rescue medications) in the first 120 h of the first cycle of emetogenic chemotherapy. Subjects were allowed to continue study treatment if they continued to meet eligibility requirements. Laboratory tests and adverse events were reported and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 for the safety population (with Grade 1, ALT > ULN to 2.5 ULN; Grade 2, ALT > 2.5–5 ULN; Grade 3, ALT > 5–20 ULN; Grade 4, ALT > 20 ULN; Grade 5, death). All subjects who received any investigational product constituted the safety population for the safety analyses. Liver chemistries were obtained pretreatment during screening, treatment days 6–10, and at completion of each cycle. Liver injury events were categorized by type of liver injury as hepatocellular, mixed or cholestatic (Danan and Benichou, 1993). Subjects with ALT elevations greater than or equal to 3 times upper limit of normal (ULN) were identified for the analysis. Cases were then excluded if there was no subsequent dosing following the ALT elevation or if the initial reported ALT elevation never recovered or failed to decrease prior to subsequent dosing. A ‘‘positive” rechallenge was defined as an elevation of ALT P 3 ULN during the treatment phase, with a recovery (or decrease) of P50%, that was followed by a recurrent elevation of ALT P 2 ULN following subsequent administration of investigational product (Danan and Benichou, 1993), and was temporally associated with dosing. A ‘‘negative” rechallenge was defined as an elevation of ALT P 3 ULN during the treatment phase that was not associated with a recurrent elevation (ALT P 2 ULN) following subsequent additional dosing of investigational product (Danan and Benichou, 1993). Published positive rechallenge cases were assessed with respect to liver injury type, timing of drug administration with respect to liver injury and results of positive rechallenge as previously defined (Benichou et al., 1993). 3. Results 3.1. Casopitant Phase III clinical trials In the Phase III study of moderately emetogenic chemotherapy, NKV102549, 1933 predominantly female subjects (98%), of median
age 52, diagnosed with breast cancer (96%) and scheduled to receive an anthracycline and cyclophosphamide-based chemotherapy were enrolled and randomized 1:1:1:1 to placebo (n = 483), casopitant single oral dose (n = 483), casopitant 3 day oral dose (n = 483), or casopitant 3 day intravenous/oral dose (n = 484) treatments (Herrstedt et al., 2009). All subjects who received any investigational product constituted the safety population (n = 1890) for the safety analyses. In the Phase III study of highly emetogenic chemotherapy, NKV102551, 810 predominantly male subjects (67–69%), of median age 58, diagnosed with a variety of solid tumors (with nonsmall cell lung cancer in >50%), and predominantly cisplatin-based (98–99%) chemotherapy were enrolled and randomly assigned 1:1:1 to receive placebo (n = 269), casopitant single oral dose (n = 271), or casopitant 3 day intravenous/oral dose (n = 270) treatments (Grunberg et al., 2009). The safety analysis included all subjects in the safety population (n = 788). Liver chemistries were generally similar across treatment groups in both studies, with 2% or fewer Grade 3 ALT elevations in any treatment group (Table 1). Of more than 2500 subjects, only three subjects exhibited ALT P 3 ULN with concomitant bilirubin P 2 ULN; all were in the highly emetogenic chemotherapy study (where two received placebo and the remaining subject with progressive biliary carcinoma received a single oral dose of casopitant). Across both studies, ALT P 3 ULN was observed in 91 subjects receiving casopitant or placebo and anti-cancer chemotherapy. Of these 91 subjects, 53 subjects did not have subsequent dosing following the ALT elevation and one subject had no recovery from the ALT elevation between dosing. These subjects were therefore excluded from the rechallenge analysis. The remaining 37 subjects met rechallenge criteria: 10 exhibited positive rechallenge (i.e., with a recurrent ALT elevation post-redosing), and 27 subjects had a negative rechallenge (i.e., no recurrent ALT elevation with subsequent dosing). A positive rechallenge was observed in similar proportions in the casopitant and placebo groups: 28% (8 of 29) in the casopitant treatment groups overall, compared with 25% (2 of 8) in the placebo group (also receiving ondansetron and dexamethasone) (Table 2). In the placebo group, peak ALT with rechallenge was less than 3 ULN. In all subjects with positive rechallenge in the casopitant treatment groups, peak ALT was less than 10 ULN for the primary and rechallenge events (Fig. 1 provides representative graphs). No liver-related serious adverse events or hypersensitivity reactions associated with the positive rechallenge were reported in any treatment group. 3.2. Rechallenge events with marketed drugs In prospective and retrospective drug rechallenge series (Andrade et al., 2009a,b; Papay et al., 2009), hepatocellular injury and jaundice were most common, antibiotics were the most frequent suspect medication, and most drug rechallenges were inadvertent. When compared to the initial liver injury, rechallenge was generally associated with a shorter time interval to recurrent liver injury. Many drugs associated with serious positive or fatal rechallenge are associated with mitochondrial impairment, hypersensitivity or immunoallergic injury and reactive metabolites. 4. Discussion Cyclic administration of casopitant or placebo (with concomitant ondansetron and dexamethasone) in two Phase III studies of chemotherapy-induced nausea and vomiting was associated with ALT > 5 ULN in up to 2% of subjects. In the absence of casopitant, ondansetron is generally associated with mild, transient, asymptomatic transaminase elevations > 2 ULN, which may recur
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C.M. Hunt et al. / Regulatory Toxicology and Pharmacology 58 (2010) 539–543 Table 1 Summary of maximum ALT in all cycles (safety populationa). Dose group
n
ALT – NKV102549 moderately Control Single dose oral 3-Day oral 3-Day IV/oral
Grade 0, n (%)
emetogenic chemotherapy 471 316 (67) 474 324 (68) 474 296 (62) 471 307 (65)
ALT – NKV102551 highly emetogenic chemotherapy Control 261 161 (62) Single dose oral 263 151 (57) 3-Day IV/oral 264 160 (61)
Grade 2, n (%)
Grade 3, n (%)
Grade 4, n (%)
134 122 157 137
21 26 16 19
(4) (5) (3) (4)
0 2 (<1) 5 (1) 7 (1)
0 0 0 1 (<1)
10 (4) 17 (6) 23 (9)
5 (2) 3 (1) 1 (<1)
0 0 0
(28) (28) (33) (29)
85 (33) 92 (35) 80 (30)
Safety population subjects with liver chemistry data.
Treatment groups Control, n
Study NKV102551, n = 15 Positive rechallenge Negative rechallenge Study NKV102549, n = 22 Positive rechallenge Negative rechallenge
2 2
Single dose oral, n
3-Day oral, n
0 2
3-Day IV/ oral, n 6 3
10 9
Exposure ALT(SGPT) AST(SGOT) TOTAL BILIRUBIN
8 7 6 5 4 3 2 1 0
0 4
0 7
2 3
0 6
Combined analyses, n = 37 Positive rechallenge 2 Negative rechallenge 6 % Positive rechallenge 25
0 9 0
2 3 40
6 9 40
with readministration in some subjects receiving cyclophosphamide-based chemotherapy (DailyMed); hypersensitivity with ondansetron rechallenge has been reported (Papay et al., 2009). In the casopitant Phase III studies, 91 subjects received investigational agent (casopitant or placebo) and experienced ALT P 3 ULN. Of these 91 subjects, only 10 subjects across all groups met positive rechallenge criteria. Similar numbers (25–28%) of positive drug rechallenge liver events were observed in the casopitant and placebo groups and none were accompanied by hypersensitivity symptoms or hospitalization. So, positive rechallenge was generally well tolerated in all subjects. In some subjects, a pattern consistent with adaptation or tolerance on positive rechallenge was observed (as portrayed in Fig. 1). These clinically unremarkable casopitant rechallenge data are presented to enhance the understanding of drug rechallenge events following potential drug-induced liver injury in controlled clinical trials. Very few controlled studies of drug rechallenge have been published; most published data arises from inadvertent rechallenge reported in case series highlighting severe or fatal events (suggesting a likely publication bias). So, while the casopitant rechallenge data provides quite limited case numbers and exclusively asymptomatic transaminase elevations, it provides useful controlled comparative data to augment the rechallenge evidence base. In contrast to published rechallenge data on marketed drugs, casopitant rechallenge was not associated with serious liver injury or fatality, hypersensitivity or immunoallergic injury, or significant mitochondrial impairment. Typically, fewer than 1 in 1000 exposed patients develop severe drug-induced liver injury (Kaplowitz, 2005), suggesting a heightened vulnerability in those affected, which may be due to a concurrent, potentially transient, inflammation (Roth et al., 2003; Cosgrove et al., 2009) and resultant oxidative stress, concomitant medications contributing to defective regeneration/repair (Suzuki et al., 2009), high drug dose or hepatic metabolism (Lammert
-25
0
25
50
75
100
50
75
100
50
75
100
StudyDay
b Liver Ch he emisttrie es (/U UL LN))
Rechallenge response
a Liver Ch he emisttrie es (/U UL LN))
Table 2 Summary of rechallenge assessments (safety population) for Phase III studies: NKV102551 (highly emetogenic chemotherapy study) and NKV102549 (moderately emetogenic chemotherapy study).
10 9
Exposure ALKALINE PHOSPHATASE ALT (SGPT) AST (SGOT) TOTAL BILIRUBIN
8 7 6 5 4 3 2 1 0
-25
0
25
StudyDay
c Liv ver Ch C em mis strries (/U ( ULN N)
a
Grade 1, n (%)
10 9 8 7 6 5 4 3 2 1 0
Exposure ALKALINE PHOSPHATASE ALT (SGPT) AST (SGOT) TOTAL `BILIRUBIN
-25
0
25
Study Day Fig. 1. (a–c) Liver chemistry elevations are profiled in three subjects receiving repeated exposures (or rechallenges) of casopitant with concomitant ondansetron, dexamethasone and emetogenic chemotherapy over time. (c) (last slide) Profiles a subject with evidence of adaptation or tolerance, with diminishing ALT elevations on repeated rechallenge.
et al., 2010), female gender or obesity (Podevin and Biour, 1995), genetic susceptibility (Andrade et al., 2009a,b), or other factors. Mitochondrial impairment (Hanley et al., 2002; Mansouri et al., 2003; Tapner et al., 2004; Ohlson et al., 2004) and immunoallergic injury (e.g. drug-specific HLA associated with hepatotoxicity, signs or symptoms of hypersensitivity, or drug-associated antibodies) (Podevin and Biour, 1995) were frequently reported among drugs with positive or fatal rechallenge and likely increase the risk of rechallenge. In particular, cumulative mitochondrial impairment
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likely increases the risk of positive rechallenge, resulting in more rapid rechallenge injury (Jones et al., 2010). Fatal halothane rechallenge events are widely attributed to immune-mediated liver injury due to the rapidity of injury with rechallenge (particularly with rechallenge within 4 weeks of primary injury) and associated fever, eosinophilia, and anti-liverkidney-microsomal (anti-LKM-1) and adduct antibodies (Uetrecht, 2008; Podevin and Biour, 1995). Halothane-associated mitochondrial inhibition is also reported (Hanley et al., 2002; Ohlson et al., 2004). Immunoallergic injury and cross-sensitization have been reported for anticonvulsants (Shear and Spielberg, 1988) and antidepressants (DeSanty and Amabile, 2007). HLA markers highly associated with liver injury have recently been reported for antibiotics and drugs of diverse classes (Nelson, 2010; Spraggs, 2010; Daly et al., 2009; Kindmark et al., 2008; O’Donohue et al., 2000). In clinical development, drug rechallenge most frequently arises in oncology trials, where drug is typically withheld when Grade 3–4 toxicity arises yet there’s evidence of benefit resulting in interest in readminstration/rechallenge when the toxicity resolves. While published data is limited and likely biased to more severe clinical outcomes, the presence of concomitant mitochondrial impairment and immunoallergic injury appear most associated with fatal or positive rechallenge, while the absence of these factors may suggest a more favorable rechallenge outcome. The cumulative effects of other risk factors such as oxidative stress, reactive metabolites, intraindividual or environmental factors, effects of infection/inflammation or comedications on drug rechallenge events remain incompletely characterized. More data is needed to examine these factors which could be obtained through publication of ‘‘inadvertent” rechallenge data from clinical trials (e.g. of drugs with cyclic adminstration) or global drug-induced liver injury registries. Such an expanded evidence base could identify additional targeted risk factors to predict clinically important positive rechallenge events, which could be instrumental in assessing possible rechallenge of critical medicines. 5. Conclusions Analysis of controlled clinical trial events reveals positive rechallenge occurring at a similar rate in those receiving casopitant or placebo in two Phase III studies, with no serious clinical outcomes or Grade 4 ALT elevations. In contrast, review of published case series suggest that drugs causing mitochondrial, immunoallergic and hepatocellular injury are associated with a higher rate of clinically important and even fatal positive rechallenge reactions. Cumulative mitochondrial dysfunction may particularly increase the risk of positive rechallenge when a suspect drug is restarted within weeks of the primary injury. So, drug rechallenge should generally be avoided and considered only if the benefit exceeds the risk (e.g. life-saving drug). Publication of drug-specific rechallenge information from controlled clinical trials and liver injury registries will further elucidate risk factors for positive rechallenge. Understanding risk factors and mechanisms of primary and rechallenge liver injury, as well as clinical outcomes, through an expanded evidence base, will advance drug safety. Conflict of interest statement All authors are fully employed by GSK. Acknowledgments The authors wish to thank the Casopitant Project Team, Steve Lane, Jon Lyon, and the GSK Hepatotoxicity Board for their expert input and Cynthia Traynham for her administrative assistance.
The corresponding author affirms that she has listed everyone who contributed significantly to the work.
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