Ciprofloxacin enhances therapeutic levels of voriconazole through CYP450 inhibition in the common raven (Corvus corax), possibly improving efficacy against aspergillosis: a pilot study

Sharmie D. Johnson Department of Veterinary Services, Wildlife World Zoo, Aquarium & Safari Park, Litchfield Park, AZ

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Andreas Lehner Section of Toxicology, Michigan State University Veterinary Diagnostic Laboratory, Michigan State University, Lansing, MI

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Levent Dirikolu Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA

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John Buchweitz Section of Toxicology, Michigan State University Veterinary Diagnostic Laboratory, Michigan State University, Lansing, MI

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Abstract

OBJECTIVE

To determine if a cytochrome (CYP) P450 enzyme inhibitor can maintain therapeutic plasma levels of voriconazole when administered orally.

ANIMALS

11 healthy, common ravens (Corvus corax).

METHODS

Birds were randomly assigned to pilot study groups to receive voriconazole orally alone or combined with a CYP inhibitor. Pilot studies with 3 CYP inhibitors launched the main study using ciprofloxacin (20 mg/kg) followed 1 hour later by voriconazole (6 mg/kg) every 12 hours for 14 days. Plasma voriconazole concentrations were measured at various time points by HPLC-MS. The study period lasted from September 2016 to December 2020.

RESULTS

The birds failed to maintain therapeutic plasma levels of voriconazole during multidose administration alone or following preadministration with various CYP inhibitors. For the 14-day study period, voriconazole reached a maximum plasma concentration of 2.99 μg/mL with a time-to-peak drug concentration of 1.2 hours following preadministration of ciprofloxacin. One bird was removed from the study due to lethargy, but the other birds completed the study without incident.

CLINICAL RELEVANCE

Ciprofloxacin (20 mg/kg) followed by voriconazole (6 mg/kg) maintained the concentration of voriconazole within the recommended therapeutic range of 0.5 to 5 μg/mL without toxicity. Ciprofloxacin prevented the saturable metabolism of voriconazole and maintained these levels for the study duration. This drug combination could be used in the treatment of chronic aspergillosis in the common raven.

Abstract

OBJECTIVE

To determine if a cytochrome (CYP) P450 enzyme inhibitor can maintain therapeutic plasma levels of voriconazole when administered orally.

ANIMALS

11 healthy, common ravens (Corvus corax).

METHODS

Birds were randomly assigned to pilot study groups to receive voriconazole orally alone or combined with a CYP inhibitor. Pilot studies with 3 CYP inhibitors launched the main study using ciprofloxacin (20 mg/kg) followed 1 hour later by voriconazole (6 mg/kg) every 12 hours for 14 days. Plasma voriconazole concentrations were measured at various time points by HPLC-MS. The study period lasted from September 2016 to December 2020.

RESULTS

The birds failed to maintain therapeutic plasma levels of voriconazole during multidose administration alone or following preadministration with various CYP inhibitors. For the 14-day study period, voriconazole reached a maximum plasma concentration of 2.99 μg/mL with a time-to-peak drug concentration of 1.2 hours following preadministration of ciprofloxacin. One bird was removed from the study due to lethargy, but the other birds completed the study without incident.

CLINICAL RELEVANCE

Ciprofloxacin (20 mg/kg) followed by voriconazole (6 mg/kg) maintained the concentration of voriconazole within the recommended therapeutic range of 0.5 to 5 μg/mL without toxicity. Ciprofloxacin prevented the saturable metabolism of voriconazole and maintained these levels for the study duration. This drug combination could be used in the treatment of chronic aspergillosis in the common raven.

Aspergillosis is a common fungal disease responsible for high morbidity and mortality in birds.1 Economic losses in production farms, zoological institutions, wildlife centers, and the pet industry can be high. Penguins,2 waterfowl,3 and birds of prey4 are particularly susceptible to disease, but any avian species is vulnerable and can be infected if immunosuppressed or exposed to environmental or social stressors such as confinement.1

Aspergillus spp are ubiquitous filamentous fungi inhabiting warm, damp regions.5 Moldy hay, grains, and decaying vegetation are common sources.5 Birds become infected through inhalation of spores, which colonize the pulmonary system and potentially disseminate to other areas in the body.1 Mycotoxins allow the organism to evade phagocytic killing.6 These toxins are responsible for the protracted treatment course in human and veterinary patients, and available antifungal medications are potentially toxic or ineffective.

Aspergillosis can cause disease in captive common ravens (Corvus corax).7 The common raven is a large passerine, 1 of the 120 known species of the Corvidae family. These birds are commonly treated at wildlife rehabilitation centers for injuries or toxicosis. Stress associated with captivity, preexisting comorbidities, trauma, and prolonged medical treatment predisposes these birds to aspergillosis.

Voriconazole is the drug of choice for the treatment of aspergillosis in humans8 and has shown potential usefulness in birds, including ravens.7 It is a second-generation triazole that inhibits fungal cytochrome (CYP) P450-dependant 14-α-demethylase, preventing the formation of the fungal cell wall, due to the reduction of ergosterol synthesis.9,10 The pharmacokinetics (PK) of voriconazole are difficult to predict due to interpatient variability and nonlinear nature.11 Voriconazole use in ravens is complicated by its unpredictable metabolism leading to potential toxicity or subtherapeutic dosing. This has been observed in some species of birds12,13 and mammals.14 To prevent rapid metabolism of voriconazole researchers have tried various medications as inhibitors in humans.1517 Inhibition of metabolism through the use of CYP inhibitors is in its infancy in veterinary medicine compared with human medicine.18

Fluoroquinolones, including ciprofloxacin, are known CYP inhibitors19 and have potential benefits in birds with aspergillosis, but caution must be exercised to prevent toxic drug-drug interactions, and therapeutic drug monitoring is recommended during use.

This study's objective was to determine if a CYP inhibitor can maintain voriconazole plasma levels above 0.5 to 1 μg/mL for extended periods in the common raven. CYP inhibitor dose and dose schedule determination in conjunction with voriconazole could have a significant positive benefit for treating ravens diagnosed with aspergillosis.

To the authors' knowledge, this is the first study of its kind in a member of the Corvidae family or Passeriformes in general.

Methods

Animals

Eleven adult nonreleasable common ravens (6 males and 5 females), with body weights ranging from 0.73 to 1.7 kg (mean, 0.94 kg) were used in this study. The birds were housed outdoors, 2 per enclosure and 1 single bird, in 6 separate enclosures at an animal sanctuary. US Fish & Wildlife Service Region 2 and Arizona Game & Fish Department provided the birds. Gender was determined by feather DNA (Animal Genetics; Avian Biotech). All participating birds were housed at the sanctuary for more than 1 year and were considered nonreleasable based on physical disfigurement that precluded flight. Inclusion in the study required the birds to be free of clinical disease, have normal hematologic and serum biochemical analytes, and have normal physical examination findings, excluding the aforementioned impediments. All 11 birds passed the inclusion requirements. A commercial diet (ZuPreem FruitBlend with Natural Fruit Flavors; ZuPreem) was supplemented with rodents, produce, and insects on a daily basis. Water was ad libitum. The birds were physically examined and weighed at the start and conclusion of the study and visually inspected twice daily. Hematology and biochemistry values, including resting serum bile acid concentrations, were obtained on each bird, initially and at the termination of each pilot and main study. Physical examination and laboratory evaluation determined the birds to be healthy with normal laboratory parameters pre- and postadministration of drugs throughout the study. Institutional Animal Care and Use Committee of Wildlife World Zoo, Aquarium & Safari Park, La Paloma Animal Sanctuary, US Fish & Wildlife Service Region 2, and Arizona Game & Fish Department Wildlife Center approved the study, and raven-specific procedures were performed in accordance with the ethical standards of the institution where the study was conducted.

Drug suspension formulations and application

All suspensions were compounded using 37.5 mL of a suspending agent (ORA-Plus Suspending Vehicle; Paddock Laboratories) with 12.5 mL of deionized water as described previously.7 Drugs were in tablet formulation and crushed with a mortar and pestle. The resulting powder was then added to the suspending vehicle and stored in an amber bottle. All suspensions were manually mixed for 2 minutes, refrigerated overnight at 4 °C, and administered the following morning. Each drug was manually shaken for 1 minute before administration.

Preliminary and primary studies used the following drug concentrations: 4 mg/mL cimetidine (Tagamet HB200; Prestige Brands Co; 1X 200-mg tablet), 10 mg/mL ciprofloxacin (500 mg ciprofloxacin; Unique Pharmaceutical Laboratories; 1X 500-mg tablet), and 4.5 mg/mL enrofloxacin (22.7-mg enrofloxacin-flavored tablets; Putney, Inc; 10X 22.5-mg tablets). A separate preliminary trial used a commercially prepared omeprazole suspension (2 mg/mL omeprazole; powder for oral suspension; Rosemont Pharmaceuticals Ltd). A 10-mg/mL concentration of voriconazole (voriconazole tablets; Sandoz Inc; 10X 50-mg tablets) was compounded and used throughout. Generic voriconazole was used because ravens are frequently treated in wildlife rehabilitation centers operating with limited budgets. The generic voriconazole is less expensive and is as effective.

Suspensions were administered with a 15-cm, curved, 10-gauge ball-tip feeding tube. The volume capacity was determined before use such that the required volume was administered and not lost in the tube.

Sample acquisition and preparation

Birds were randomly chosen for each study. Each bird's house name identification was placed in a box and chosen blindly and then assigned sequential numbers for simplicity. The birds were administered the designated amount of voriconazole alone or with a CYP inhibitor in succession in pilot studies 2 and 3 and 1 hour apart in the primary group (ciprofloxacin followed by voriconazole). The birds were fed and offered water 1 hour later following blood collection. One-half milliliter of blood (0.5 mL) was collected from each bird at each time point. Except for pilot study 2, blood samples were collected at 12 and 24 hours following voriconazole administration. For pilot study 2, blood collection was performed at 12 and 24 hours for one bird and 6 and 18 hours for the other bird. For all studies, blood collection was performed on day 0 (induction) and days 3, 7, 10, and 14. Following final drug administration on day 14, blood was collected at 24, 48, and 72 hours. Blood samples were obtained from the right jugular or metatarsal veins and placed into lithium heparin microtainers. Plasma was decanted within 20 minutes (10 minutes postdraw, 10 minutes postcentrifugation at 3,400 X g) and stored at −80 °C until shipment to the lab on dry ice at the conclusion of the study period. The drug suspensions were refrigerated at 4 °C between administrations and then frozen at the time of the final administration for concentration determination and shipped with the plasma samples. Blood and plasma were submitted for hematology and biochemical evaluation at the conclusion of the study period.

Pilot studies

The objective of the pilot studies was to determine an appropriate oral (PO) dose and frequency of voriconazole administration (Table 1). The treatment duration for each pilot study was 14 days. The study period was September 2016 to April 2018.

Table 1

Dosing schedule for all studies involving multidose treatment of 11 healthy, nonreleasable common ravens (Corvus corax) (birds 1 to 11) with voriconazole in the presence or absence of cytochrome (CYP) inhibitors (ciprofloxacin, enrofloxacin, cimetidine, or omeprazole).

Study/animal designation CYP inhibitor Voriconazole induction dose (mg/kg) Voriconazole maint dose (mg/kg) CYP inhibitor induction dose (mg/kg) CYP inhibitor maint dose (mg/kg) Dosing interval (h)
Pilot 1: voriconazole alone
 1 None 10 5 n/a n/a 24
 2, 3 None None 10 n/a n/a 24
 4 None 24 12 n/a n/a 12
 5, 6 None None 20 n/a n/a 24
Pilot 2: voriconazole with cimetidine, ciprofloxacin, or enrofloxacin
 7 Ciprofloxacin 12 6 10 5 24
 9, 10 Enrofloxacin 12 6 20 10 24
 8 Cimetidine 12 6 10 5 24
Pilot 3: voriconazole with cimetidine or omeprazole
 7, 8 Cimetidine 24 12 10 5 12
 6 Omeprazole 24 12 2 1 12
Main study: voriconazole with ciprofloxacin
 2, 3, 5, 6, 9, 11 Ciprofloxacin None 6 None 20 12
 1, 2 Ciprofloxacin None 18 None 20 12

Voriconazole doses ranged from 5 to 24 mg/kg, PO, every 12 to 24 hours for 14 days and were administered 1 hour following a CYP inhibitor. The study was conducted from September 2016 to December 2020.

Maint = Maintenance. n/a = Not applicable.

Pilot study 1: voriconazole alone (birds 1, 2, 3, 4, 5, and 6)—Three separate studies were evaluated using either a single bird or a pair of birds. Doses were extrapolated from the IV and single PO dose studies used in a previous study.7

Pilot study 2: Voriconazole with CYP inhibitors—voriconazole with cimetidine (bird 8), voriconazole with ciprofloxacin (bird 7), or voriconazole with enrofloxacin (birds 9 and 10)—This study focused on voriconazole with cimetidine (bird 8), ciprofloxacin (bird 7), or enrofloxacin (birds 9 and 10).

Pilot study 3: Voriconazole with CYP inhibitors—voriconazole with cimetidine (birds 7 and 8) or voriconazole with omeprazole (bird 6)—The focus of this study was on the CYP inhibitory effects of cimetidine and omeprazole. Two birds were from pilot study 2 following a 1-month washout period (birds 7 and 8), and 1 bird was from pilot study 1 following an 11-month washout period (bird 6).

Primary multidose study

Two separate studies were evaluated using 4 pairs of birds 9 months after pilot study 3 was completed. Doses were based partly on the results of pilot study 2 and a single-dose study performed earlier.7 The drugs were administered PO every 12 hours. Birds were fasted for 12 hours, administered the last morning dose, and fed 1 hour later. The feeding schedule adhered to their normal prestudy schedule. Water was available but removed 1 hour before the evening dose. Ciprofloxacin (20 mg/kg) was followed 1 hour later by voriconazole. Birds 1 and 2 received voriconazole (18 mg/kg), and birds 2, 3, 5, 6, 9, and 11 were administered voriconazole (6 mg/kg). Blood was drawn as previously described on days 0, 1, 3, 7, 10, 14, 15, 16, and 17 unless noted otherwise. Samples were obtained before the next dosing and again at 1, 6, and 12 hours postvoriconazole administration unless stated otherwise. The samples drawn represented hours 2, 7, and 13 postciprofloxacin administration. All the birds excluding bird 11 had previously participated in pilot studies (birds 1, 2, 3, 4, 5, 6, and 9). Bird 2 participated in the low and high-dose studies (December 2020 and January 2019, respectively). The study period was from January 2019 to December 2020 (Table 1).

Determination of drug concentration and method validation

The method for voriconazole concentration determination and its validation have been published.7 Briefly, the method relied on HPLC coupled with tandem mass spectrometry in electrospray ionization + mode (Thermo-Finnigan Surveyor HPLC-TSQ Quantum ESI-MS/MS Detector; Thermo Fisher Scientific).

Multiple Reaction Monitoring for voriconazole detection involved fragmentation m/z 350.3 → 281.2 and → 127.5 with a collision energy of 20 eV and a tube lens of 200 V. One-half milliliter of plasma was protein precipitated and simultaneously extracted by the addition of 1-mL acetonitrile. Standard dilutions in water were prepared at concentrations ranging from 0.5 to 100 μg/mL for calibration curve generation for unknown interpolation. Chromatography was performed on a column (Alltech Alltima; 3-μm, 2.1 X 50-mm C18; Thermo Fisher Scientific) with a gradient of 0.1% formic acid in HPLC-grade water (solvent A) and HPLC-grade acetonitrile with 0.1% formic acid (solvent B) at 300 μL/min throughout with development as follows: 90% A/10% B (0 to 2 minutes); linear gradient to 10% A/90% B (2 to 7 minutes); held at 10% A/90% B (7 to 9 minutes); linear gradient to 90% A/10% B (9 to 10 minutes); and held at 90% A/10% B (10 to 13 minutes).

PK calculations

Data were evaluated by use of a noncompartmental analysis using Phoenix Winnonlin (version 8.1; Certara) to determine standard PK parameters, including terminal rate constant, terminal half-life, time to maximum plasma concentration (tmax), maximum plasma drug concentration (Cmax), mean residence time, predicted area under the curve of the concentration-time curve from time 0 to infinity, area under the first moment curve from time 0 to infinity, and area under the first moment of the concentration-time curve from time 0 to infinity (AUC0-∞). The program assumed first-order kinetics based on the linearity of the terminal portion of the semilogarithmic concentration-time plots.

Results

Birds

Ten of the 11 birds completed the trials and maintained pretreatment weights. One male raven (bird 1) was removed from the main study on day 7 due to lethargy and hyporexia beginning on day 5. Hct, total protein, albumin, AST, uric acid, and resting bile acids remained in the normal range and a coccidia infection was diagnosed on fecal examination. All study drugs were discontinued at this time, and the bird returned to normal following the elimination of the endoparasite with an anticoccidial drug. No abnormal behaviors were observed in any of the remaining birds, and clinically relevant blood parameters including Hct, total protein, albumin, AST, uric acid, and resting bile acids remained stable. The birds tolerated the procedures well, and physical examination findings remained unchanged.

Drug stability

Analysis of voriconazole concentration at the end of the study showed the suspensions to be stable. Dosage forms were checked for the appropriate concentration at 10 mg/mL by determination of values from 1:100 dilutions, and results were measured at 9.712 ± 0.941 mg/mL to 1 SD.

PK parameters were calculated using a noncompartmental method. Plasma concentrations versus time curves were developed from the 2 multidose studies using 20 mg/kg of ciprofloxacin with 6 or 18 mg/kg of voriconazole administered every 12 hours (Figure 1).

Figure 1
Figure 1
Figure 1
Figure 1

Mean plasma disposition of voriconazole administered orally (PO) in the common raven (Corvus corax) at different concentrations in the absence and presence of ciprofloxacin using a noncompartmental model. Plasma concentrations dropped below the target minimum therapeutic level (0.5 to 1 μg/mL) for the majority of the sampling time points for the birds receiving voriconazole without a cytochrome (CYP) inhibitor. A—Average results for 2 ravens administered voriconazole 10 mg/kg, every 24 hours without a CYP inhibitor. B—Average results for 6 ravens (birds 1 to 6) across all dosing regimens with 5, 10, 12, and 20 mg/kg of voriconazole without a CYP inhibitor. C—Pharmacokinetic parameters determined from the average of 6 ravens (birds 2, 3, 5, 6, 9, and 11) using a noncompartmental model for voriconazole administered at a dose of 6 mg/kg measured in the presence of 20 mg/kg of ciprofloxacin, 1 hour prior. Both drugs were administered every 12 hours for 14 days. The longer dashed line indicates the threshold for the minimum therapeutic value for voriconazole in each case; the shorter dashed line indicates the polynomial trendline for voriconazole concentrations in each case.

Citation: American Journal of Veterinary Research 85, 5; 10.2460/ajvr.23.12.0288

Pilot study 1: voriconazole alone

None of the birds achieved concentrations of voriconazole in the therapeutic range for the duration of the study when used without a CYP inhibitor. Bird 1 was administered 5 mg/kg and had the lowest tmax of 12 hours. Birds 2 and 3 were administered the 10-mg/kg maintenance dose and had a Cmax of 1.73 μg/mL and a tmax of 42 hours. Birds 5 and 6 administered 20 mg/kg showed an almost 10-fold increase in Cmax of 16.6 μg/mL with a tmax of 24 hours. Bird 4 was administered 12 mg/kg twice a day. The Cmax was 2.5 μg/mL with a tmax of 48 hours. This was the only bird to maintain therapeutic values up to day 7, and levels decreased below this in the other birds by 60 hours (Figure 2).

Figure 2
Figure 2

Maximum observed concentration (Cmax; solid) and time taken to reach (tmax; hatched) values for the different dosing regimens of voriconazole in common ravens (birds 1 to 6) in the absence of cytochrome inhibitors during the initial 72-hour postinitial dose. Only 1 of the 6 ravens was able to maintain therapeutic values up to day 7 and levels decreased below this in the other birds by 60 hours. Experiment labels indicate initial dose followed by the maintenance dose (in mg/kg). The dosing interval was 24 hours throughout. The experiments involved birds 1, 2, 3, 4, 5, and 6. Init = Initial dose. Maint = Maintenance dose.

Citation: American Journal of Veterinary Research 85, 5; 10.2460/ajvr.23.12.0288

Pilot study 2: voriconazole with CYP inhibitors (cimetidine, ciprofloxacin, or enrofloxacin)

Bird 7 (ciprofloxacin) had a plasma concentration of voriconazole in the potentially toxic range at days 3, 7, and 14 (Table 1). Bird 8 (cimetidine) was able to achieve plasma voriconazole concentrations above 0.5 μg/mL at various time points to day 14. Birds 9 and 10 (enrofloxacin) were sampled at 12 and 24 hours and 6 and 18 hours (bird 10) postvoriconazole administration. Bird 9 maintained a peak plasma concentration above 0.5 μg/mL for days 1, 3, and 7. Bird 10 failed to maintain plasma concentrations above 0.5 μg/mL for the sampling period, apart from the postinduction value (Supplementary Figure S1).

Pilot study 3: voriconazole with cimetidine or omeprazole

Birds 7 and 8 (cimetidine) maintained voriconazole concentrations above 0.5 μg/mL up to days 7 and 10. A decrease in the concentration was observed beginning on day 3. Bird 6 (omeprazole) achieved occasional therapeutic levels up to day 10. Male birds 6 and 7 showed a decrease in levels starting on day 3 (Supplementary Figure S2).

Feasibility study

Pilot studies indicated the likely success of the application of ciprofloxacin as a CYP inhibitor of voriconazole metabolism. Birds 1 and 2 received a high dose (18 mg/kg) of voriconazole. Bird 1 had a Cmax of 167 μg/mL and was removed from the study on day 7 due to hyporexia and depressed demeanor. The bird resumed normal behavior 24 hours after the drugs were discontinued and treatment for coccidia was initiated. Bird 2 had a peak voriconazole concentration of 71.9 μg/mL following the first dose, which increased up to 72 hours but began to decrease from days 7 to 10. The levels never dropped below 25 μg/mL for the duration of the study. Plasma levels decreased below 0.5 μg/mL for days 15 to 17 following cessation of the drugs on day 14 (Table 2).

Table 2

Pharmacokinetic parameters for voriconazole administered PO at a dose of 18 mg/kg.

Parameter Average SD
No. animals 2
Dose (mg/kg) 18
λz (1/h) 0.05 0.011
t1⁄2 λz (h) 15.515 4.011
tmax (h) 1.2 0.4
Cmax (μg/mL) 97.4 37.7
AUC0–∞ (h·μg/mL) 2,028.7 1,318.3
MRT (h) 23.103 5.438

The average of 2 common ravens (birds 1 and 2) measured in the presence of ciprofloxacin dosed at 20 mg/kg, PO, 1 hour prior.

λz = Individual estimate of the terminal elimination rate constant. Cmax = Maximum observed concentration. AUC0–∞ = Area under the curve from the time of dosing to the time of the last observation. MRT = Mean residence time. t1⁄2 λz = Terminal half-life. tmax = Time taken to reach Cmax.

The average Cmax and tmax for the 6 birds (birds 2, 3, 5, 6, 9, and 11) receiving the low dose (6 mg/kg) of voriconazole were 3.26 ± 1.06 μg/mL and 1.3 ± 0.36 hours, respectively. The majority of the voriconazole levels for these birds fell within the recommended 0.5 to 5 μg/mL and remained there for the duration of the treatment period. The levels were subtherapeutic for days 15 to 17 in all the birds once the drugs had been discontinued (Table 3).

Table 3

Pharmacokinetic parameters determined from the average of 6 common ravens (birds 2, 3, 5, 6, 9, and 11) using a noncompartmental model for voriconazole administered at a dose of 6 mg/kg measured in the presence of 20 mg/kg of ciprofloxacin, 1 hour prior.

Parameter Average SD
No. animals 6
Dose (mg/kg) 6
λz (1/h) 0.098 0.04
t1⁄2 λz (h) 11.38 8.4
tmax (h) 1.267 0.37
Cmax (μg/mL) 3.26 1.06
AUC0–∞ (h·μg/mL) 62.51 65.21
MRT (h) 16.75 12.75

Both drugs were administered PO every 12 hours for 14 days.

λz = Individual estimate of the terminal elimination rate constant. Cmax = Maximum observed concentration. AUC0–∞ = Area under the curve from the time of dosing to the time of the last observation. MRT = Mean residence time. t1⁄2 λz = Terminal half-life. tmax = Time taken to reach Cmax.

Plasma concentration versus time curves were developed from the 2 multidose studies and included the results for the birds receiving voriconazole alone for comparison (Figure 1). Tripling the dose of voriconazole from 6 to 18 mg/kg resulted in a more than 3,100% increase in the AUC0-∞ (64.31 μg/mL/h for the 6-mg/kg dose vs 2,028.7 μg/mL/h for the 18-mg/kg dose, respectively (Tables 3 and 4). The Cmax increased by 32.6-fold (2.99 vs 97.4 μg/mL) for the 6- versus the 18-mg/kg dose. Cmax values were above 0.5 μg/mL in both groups. The tmax levels were similar in both groups, and the t1/2 was 11.8 vs 15.5 hours, respectively. These values attained the MIC of voriconazole reported for 100% of pathogenic Aspergillus spp.7 These values were compared with those from the group of birds (birds 1 to 6) that received different voriconazole doses without ciprofloxacin, and the Cmax ranged from 4.87 to 16.6 μg/mL and tmax from 12 to 48 hours. None of the birds in those groups were able to maintain levels above the recommended 0.5 μg/mL beyond 60 hours.

Table 4

Pharmacokinetic parameters averaged for 6 common ravens (birds 2, 3, 5, 6, 9, and 11) administered ciprofloxacin at a dose of 20 mg/kg, PO, every 12 hours.

Parameter Average SD
No. animals 6 6
Dose (mg/kg) 20
λz (1/h) 0.189 0.063
t1⁄2 λz (h) 4.134 1.779
tmax (h) 1.133 0.298
Cmax (μg/mL) 2.574 1.074
AUC0–∞ (h·μg/mL) 15.445 4.834
MRT (h) 5.809 2.845

λz = Individual estimate of the terminal elimination rate constant. Cmax = Maximum observed concentration. AUC0–∞ = Area under the curve from the time of dosing to the time of the last observation. MRT = Mean residence time. t1⁄2 λz = Terminal half-life. tmax = Time taken to reach Cmax.

The average Cmax and tmax for ciprofloxacin for the 6 birds receiving 6 mg/kg of voriconazole (birds 2, 3, 5, 6, 9, and 11) were 2.57 ± 1.07 μg/mL and 1.13 ± 0.29 hours, respectively. The average t1/2 was 4.13 ± 1.78 hours. AUC0-∞ was 15.45 ± 4.83 μg/mL/h, and the mean residence time was 5.80 ± 2.85 hours (Table 4). These levels were above the recommended MIC of 0.125 to 0.75 μg/mL (MIC50) and greater than or equal to 2.0 μg/mL (MIC90) for most gram-negative bacteria and mycoplasma.20

Discussion

Limited data exist on the potential efficacy or toxicity of long-term voriconazole use in the treatment of aspergillosis in common ravens. A few PK studies3,9,13,21 available for other avian species have shown corresponding variabilities in the disposition of voriconazole, particularly in multidose studies. Initial studies7 with ravens showed that bioavailability following 3 different single oral doses of voriconazole was higher when compared to other avian species tested to date and that the PK following oral and single intravenous doses was nonlinear. Administration of multiple doses of voriconazole to the ravens in that study suggested that the drug likely induces its own metabolism by 72 hours prompting questions regarding efficacy as a sole treatment for chronic aspergillosis in this species.

Voriconazole is the standard of care in human medicine for aspergillosis and is increasingly administered to avian patients.22 The nonlinear nature of voriconazole combined with interindividual variability in metabolism can result in inappropriate treatment due to either subtherapeutic or toxic doses if based on extrapolation alone. This was evident from the results observed in pilot study 1 where the birds failed to achieve target therapeutic levels using voriconazole alone regardless of the dosing strategy. Inadequate dose or poor absorption is unlikely since the birds achieved a Cmax > 1.0 μg/mL. Results reflect probable induction of the CYP system as 5 of 6 birds had subtherapeutic levels by 72 hours. Therapeutic dose monitoring is recommended for humans receiving this drug and should be performed in avian patients to manage supra- and subtherapeutic voriconazole exposure.23

Voriconazole is believed to induce its own metabolism based on the results of a study in African grey parrots.21 Enzyme induction can take from a few days to 2 to 3 weeks in humans.24 PK enhancers lead to the increased bioavailability of certain metabolized drugs, thus reducing first-pass metabolism and leading to a prolonged increase in the concentration of the corresponding drug through slower elimination.18 Chloramphenicol was successfully added as a CYP3A4 and CYP2C19 inhibitor of voriconazole in a human with aspergillosis who failed to maintain therapeutic voriconazole levels.15 Omeprazole and cimetidine have been shown to increase the voriconazole peak concentration in humans by 15% to 18.3%, respectively.16,17 The addition of a CYP inhibitor to bird 7 (ciprofloxacin) and bird 8 (cimetidine) improved the peak concentrations of voriconazole for the 14-day treatment period in pilot study 2. The raven from pilot study 3 (bird 6) produced a 37% increase following omeprazole use that was of short duration. The female raven (bird 8) maintained therapeutic levels of voriconazole following cimetidine administration for a short period, but the male (bird 7) did not. Twice-daily cimetidine or once-daily omeprazole resulted in therapeutic levels to day 10. These findings indicate minor suppression of voriconazole metabolism resulting from the addition of cimetidine and omeprazole, respectively. None of the birds maintained a plasma concentration above 0.5 μg/mL following cessation of voriconazole dosing.

Fluoroquinolones are known CYP inhibitors.19 This antibacterial drug class has been shown to inhibit CYP1A and 3A activities in several species,19,2527 and enrofloxacin has also been shown to cause inhibition of avian CYP3A.27 CYPs are enzymes responsible for the metabolism of drugs, hormones, and environmental toxins. CYPs in hepatic and other organ endoplasmic reticula are linked to feeding habits, habitats, and migration. The CYP2C and 3A subfamilies have been identified in birds and are inducible by other ergosterol biosynthesis-inhibiting antifungal drugs.3 Avian CYP families 1 to 3 are primarily involved with xenobiotic biotransformation and have been identified in several corvid species.25,2830 Closely related species probably share the same evolutionary traits in the mixed function oxidases system.31

Injured ravens are frequently cared for at wildlife rehabilitation centers. The birds may be dehydrated and are often moribund at presentation. If wounds are present, they may be several hours old and contaminated with bacteria. Fluoroquinolones provide advantages over other drug classes due to their minimal adverse effects and broad spectrum of antimicrobial activity.3234 The bioavailability of enrofloxacin can vary between avian species.3335 When enrofloxacin was studied in the raven, there was minimal CYP enzyme inhibition based on the failure to maintain therapeutic levels of voriconazole. It is possible that ravens display variable metabolism of enrofloxacin and that the gender of the bird is influential in the response.36 This was observed with birds 9 and 10 in pilot study 2. The male produced levels above the therapeutic range while the female did not.

The risk of drug-drug interactions leading to toxicity or reduced efficacy can differ depending on the individual drugs involved, even for drugs within the same class.35 This may explain the differences between enrofloxacin, ciprofloxacin, and voriconazole concentrations observed in the ravens. Enrofloxacin may not be metabolized to ciprofloxacin in the raven as occurs in most mammals37 and some birds.38

Ciprofloxacin is a second-generation fluoroquinolone commonly used for gram-negative and some gram-positive bacterial infections, Mycoplasma spp, and Chlamydia spp in humans and animals.39 Plasma concentrations of 0.125 to 0.75 μg/mL (MIC50) and greater than or equal to 2.0 μg/mL (MIC90) are recommended for most gram-negative bacteria and mycoplasma.20 Potential side effects include gastrointestinal disturbances, joint abnormalities in juvenile animals, phototoxicity, convulsions, and laboratory abnormalities.40 Ciprofloxacin is a potent inhibitor of CYP1A2 in mammals, which is orthologous to avian CYP1A5 resulting in probable inhibition of this enzyme in avian species.19,25 It competitively inhibits CYP1A and 3A in rats and humans.19,25

The average Cmax of ciprofloxacin for the common ravens in this study was 2.57 ± 1.07 μg/mL (range, 0.579 ± 0.233 μg/mL to 5.10 ± 2.50 μg/mL) following a 20-mg/kg dose, which exceeds the recommended 0.06 to 1 μg/mL as established by antimicrobial susceptibility testing.34

Red-tailed hawks administered 50 mg/kg produced a Cmax of 3.64 μg/mL, tmax of 0.92 hours, AUC of 16.6 h·μg/mL, and t1/2 of 2.49 hours.39 These results are slightly higher than those produced by the ravens administered 60% less ciprofloxacin (20 mg/kg) except for the tmax in the hawks being only slightly lower. The elimination half-life was almost doubled in the raven in comparison indicating rapid absorption and possibly reduced metabolism in this species.

Passerines have a basal metabolic rate (BMR) that is 50% to 60% higher than nonpasserines of the same size,40 and migratory and omnivorous species have a higher BMR than other species. This relatively high BMR may promote the rapid metabolism of xenobiotics.31 Detoxification ability has been found to be positively correlated with hepatic size and increased microsomal monooxygenase activity in several passerine species.31 Ravens are migratory and omnivorous, and, as one of the largest passerines, have a substantial liver.41 Its omnivorous feeding habits, relatively large size, and wide adaptability may promote a more efficient detoxification capacity.42

Ravens are adaptable to a variety of climates due to their unique ability to regulate osmotic challenges owing to a lower concentration of albumin.43 This can increase the tissue penetration and hepatic clearance of drugs like voriconazole due to reduced protein binding. Albumin accounts for 30% of protein binding of drugs in general, and voriconazole is 58% protein bound in humans.44 Voriconazole is moderately protein bound in lab animals.14 Albumin concentration is 0.2 to 2.4 g/dL and 4.0 to 5.0 g/dL in chickens and humans, respectively.45 The ravens in this study ranged from 1.1 to 3.0 g/dL. These factors may contribute to the rapid metabolism of voriconazole observed in this species during multidose studies when voriconazole is used without a CYP inhibitor. Variability in voriconazole metabolism observed can also be directly affected by gastrointestinal transit time.46 Rapid absorption is associated with morphological adaptations to the gastrointestinal tract that is unique to corvids.31

This study suggests voriconazole bioavailability was higher when combined with ciprofloxacin compared to single drug use based on the observed voriconazole plasma concentrations, duration, and levels.7 If the AUC of a drug was increased to less than or equal to 2-fold in the presence of a coadministered drug, there would be no need to make dose adjustments. Drugs with a greater than 5-fold increase indicate a strong inhibitor of metabolism and dose adjustments may be required to prevent toxicity.18 A 3-fold increase in the dose of voriconazole administered to the ravens resulted in a greater than 32-fold increase in AUC indicating that ciprofloxacin is a strong inhibitor of voriconazole metabolism. Drug-drug interactions can cause fatal effects through enzyme inhibition and drug accumulation.22 Adverse effects include fatal cardiac manifestations of ciprofloxacin-voriconazole coadministration in humans.47 Drug-drug interactions can further CYP downregulation associated with renal disease, infections, and inflammation leading to higher voriconazole trough concentrations, followed by a decrease once inflammation is resolved.22,48

Intra- and interspecies differences exist with clinical efficacy and toxicity.14 Plasma levels greater than 5 to 6 μg/mL have been associated with adverse effects in humans, and levels greater than or equal to 30 μg/mL in penguins resulted in clinical illness.2 Voriconazole administered at 18 mg/kg induced polyuria in Timneh parrots (Psittacus erithacus timneh).21 The highest Cmax observed in mallard ducks (Anas platyrhynchos) was 25.6 μg/mL following doses of 10, 20, and 40 mg/kg, PO, once daily, with no clinical toxicity.3 In the current study, elevated plasma levels were observed with voriconazole administered in combination with CYP inhibitors. A dose reduction may be indicated to prevent toxicity, but a longer study with more ravens and subsequent tissue evaluation would be required to assess appropriate dosing. Posttreatment hematology and biochemical parameters for the ravens were within normal range, suggesting a lack of acute toxicity.

The results obtained from this study concur with previous studies of voriconazole metabolism in avian species despite the limitations of a small number of available birds and relatively short duration of treatment. Aspergillosis typically causes chronic disease requiring treatment for an extended period.26 Voriconazole appears to induce its own metabolism in ravens based on this multidose study. Inhibition of this activity is directly correlated with the addition of ciprofloxacin, a known CYP1A2 inhibitor in humans.49 Ciprofloxacin-voriconazole interactions are clinically important; further investigation is needed to determine long-term effects on common ravens infected with Aspergillus spp. Future research should provide the PK of the ciprofloxacin-voriconazole combination in clinically ill ravens since infection and inflammation can markedly downregulate hepatic metabolic activity, making drugs potentially more toxic.49

Determination of an appropriate dosage regimen in a specific species is dependent on the understanding of the PK in that species.48 Voriconazole alone cannot maintain therapeutic plasma concentrations to treat aspergillosis in ravens. In contrast, combining voriconazole with ciprofloxacin provided the needed enzyme inhibition to enable therapeutic levels. Increasing concern over fluoroquinolone resistance necessitates proper use based on knowledge of the PK for these drugs in the treated species for optimal dosage regimens. Extrapolation could lead to antimicrobial resistance through suboptimal dosing. Based on the plasma concentrations for ciprofloxacin observed in the ravens, the levels fell within the established MIC for clinically relevant bacteria causing Aspergillus comorbidity.

The objective of this project was to determine if CYP inhibitors could enhance plasma levels of voriconazole in the common raven above the MIC of 0.5 to 1.0 µg/mL for the pathogenic Aspergillus species known to infect birds. Results from the pilot studies revealed that autoinduction of CYP enzymes probably caused suboptimal concentrations of voriconazole in ravens, as observed in other avian species.10 The objective was met through multiple pilot trials, ultimately leading to the multidose regimen that can be considered for the treatment of clinical cases in this species. The twice-daily dose of 6 mg/kg voriconazole combined with 20 mg/kg of ciprofloxacin maintained the plasma concentration of voriconazole within the established therapeutic range without evidence of clinical toxicity. The plasma levels for ciprofloxacin for the majority of the birds were between the established MIC50 to MIC90 for most gram-negative pathogenic organisms that are susceptible to ciprofloxacin.22

These results support further investigation of ciprofloxacin use as a CYP inhibitor when administered in conjunction with voriconazole and provide a foundation for the establishment of dosing regimens for future studies. This study contributes to furthering understanding of drug-drug interactions in veterinary medicine, an area still in its infancy.

Supplementary Materials

Supplementary materials are posted online at the journal website: avmajournals.avma.org.

Acknowledgments

We acknowledge Warren Johnson, MD, PhD, and Margaret Johnson, MS (Michigan State University).

Disclosures

The Wildlife World Zoo & Aquarium was not involved in the study design, data analysis, interpretation, writing, or publication of the manuscript.

No AI-assisted technologies were used in the generation of this manuscript.

Funding

Funding was provided by Wildlife World Zoo & Aquarium.

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