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Safety and Pharmacokinetics of a Single 1500-mg Dose of Famciclovir in Adolescents With Recurrent Herpes Labialis

Block, Stan L. MD*†‡; Yogev, Ram MD§; Waldmeier, Felix PhD; Hamed, Kamal MD, MPH

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The Pediatric Infectious Disease Journal: June 2011 - Volume 30 - Issue 6 - p 525-528
doi: 10.1097/INF.0b013e3182067cee
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Abstract

Herpes simplex virus type 1 (HSV-1) infection is typically acquired in childhood and increases in prevalence with age. Approximately 40% of American adolescents are seropositive for HSV-1, of whom 25% report recurrent episodes of herpes labialis.1 Herpes labialis lesions progress rapidly after symptom onset, with HSV titers, lesion size, and pain being greatest in the first 24 hours.2 Most lesions progress from vesicle stage to ulcer/soft crust stage within 48 hours, with a hard crust forming by day 2 or 3.3 Lesions typically last 5 to 6 days, but can range from 2 to 20 days.4 Of patients seeking treatment for a recurrence, approximately 80% cite pain or discomfort and 60% cite social stigma as their major concerns.5 Disruption of normal eating, drinking, and social interaction can create considerable psychosocial stress.6

Although HSV-1 infection cannot be cured, it can be treated episodically within 24 hours of symptom onset to decrease episode duration and associated symptoms. Famciclovir is the oral prodrug of penciclovir, which has potent and selective clinical activity against HSV-1, HSV-2, and varicella-zoster virus, and it is approved by the United States Food and Drug Administration as a single, 1500 mg dose treatment for recurrent herpes labialis in immunocompetent adults.

The safety and pharmacokinetics (PK) of famciclovir have been reported in infants, children, and adults, but not in adolescents. The current study sought to explore the safety, tolerability, and PK of a single 1500 mg dose of famciclovir in adolescents with recurrent herpes labialis. Preliminary data on patients' response to this dose were also collected.

METHODS

This was a multicenter, open-label, single-arm study of clinic-initiated, single-dose therapy with famciclovir in adolescents (12 to <18 years of age) with recurrent herpes labialis who were ≥40 kg body weight. At least 8 patients with a documented history of recurrent herpes labialis were to undergo PK assessments. PK patients could be enrolled with or without an active herpes labialis outbreak but non-PK patients were required to have an active recurrence with symptoms/lesions of onset ≤24 hours before famciclovir dosing.

Visit 1 assessments were inclusion/exclusion criteria, medical history, concomitant medications, physical examination, adverse events (AEs), review of herpes labialis symptoms, lesion assessment, laboratory safety tests, HSV serology, and HSV polymerase chain reaction on lesion swabs. Eligible patients were administered a single 1500 mg (3 tablets × 500 mg) dose of famciclovir by study personnel. PK patients were requested to fast at least 8 hours before visit 1 and for 2 hours after famciclovir dosing. For PK assessments, blood samples (1.0 mL each) were collected at predose, 0.5, 1, 1.5, 2, 3, 4, 6, and 10 hours after dosing and analyzed as previously reported.7 Safety was reviewed on day 2 or 3. An End of Study (EOS) clinic visit was scheduled on days 4 to 6 to assess lesions/symptoms for patients with an active recurrence. At the end of visit 1, non-PK patients were scheduled for visit 2 (days 3 ± 1) and visit 3 (days 5 ± 1). The EOS visit was day 5 for patients with confirmed healing of lesions, or day 7 ± 1 for patients with lesions at day 5.

Vital signs, hematology, clinical chemistry, and urinalysis were assessed at visits 1 and 3 or at premature discontinuation in non-PK patients. Vital signs, hematology, and clinical chemistry were assessed at visits 1 and EOS in PK patients. Laboratory samples were processed at a central laboratory. Safety assessments included AEs and their severity, duration, and relationship to study drug. AEs were treated as appropriate and followed until resolution.

Efficacy assessments included time to healing of nonaborted lesions and all lesions, and overall response to treatment. At visit 1 and at EOS visit or premature discontinuation, presence/absence of symptoms was assessed. Lesion stages and time to healing were recorded for non-PK patients and overall treatment response was recorded for all patients. Lesion healing was defined as loss of crust and reepithelialization.

RESULTS

In this study, 43 non-PK patients and 10 PK patients were enrolled. Two PK patients withdrew consent but were included in the safety assessments. Patient demographics and baseline disease characteristics are presented in Table 1. Approximately 30% of patients took concomitant medications either within 2 days before study drug or during the study, the most common being contraceptives and ibuprofen. All patients took the full dose of famciclovir in the clinic. The median time to dosing from the time of onset of symptoms was 20.7 hours.

TABLE 1
TABLE 1:
Patient and Disease Characteristics at Baseline

AEs were reported by 23% (12/53) of patients, the most common being dizziness (3 patients) and headache (2 patients). All other AEs were reported for 1 patient each. AEs were reported as either mild or moderate. Moderate AEs were not considered drug related and consisted of 1 case of fatigue, nausea, and vomiting, and 1 case of lymphadenopathy. Mild AEs suspected to be drug related consisted of 1 case each of headache, pollakiuria, diarrhea, and dizziness, and 1 case of headache and dizziness. Four mild AEs that required significant additional therapy were dysmenorrhea, upper abdominal pain, anemia, and headache (for the case of headache and dizziness). Only headache was suspected as drug related. No clinically meaningful shifts from baseline in hematology and clinical chemistry values were noted.

Mean plasma concentration time profiles of penciclovir for 8 patients are presented in Figure 1. Mean Cmax, mean AUC0-∞, clearance, and t1/2 for penciclovir were 9.37 μg/mL (standard deviation [SD]: 2.68), 31.8 μg · h/mL (SD: 5.53), 38.2 L/h (SD: 6.1), and 1.81 hours (SD: 0.22), respectively. Peak concentrations of penciclovir occurred at a median of 1 hour after dosing.

FIGURE 1.
FIGURE 1.:
Mean (±SD) plasma concentration-time profiles of a 1500 mg dose of penciclovir in adolescents versus extrapolated data from adults. Adult data are from a study of 24 healthy volunteers (mean age, 34 years [SD: 7]; mean body weight, 75.6 kg [SD: 7.9]) in a fasted state who received a single 500 mg oral dose of famciclovir. Data on file, Novartis. *Data points have been shifted 0.05 hours to enhance visibility.

These data were compared with historic data from 24 healthy adult volunteers after a single 500 mg dose of famciclovir,7 extrapolated to a 1500 mg dose and assuming dose proportionality of systemic exposure. Mean plasma concentration time profiles of penciclovir were similar between adolescents and adults (Fig. 1). The Cmax and AUC0-∞ values observed for penciclovir in adolescents were within the range of values extrapolated from adults (Cmax, 10.34 μg/mL [SD: 2.45]; AUC0-∞, 26.81 μg · h/mL [SD: 5.07]).7 The clearance of penciclovir observed in adolescents (38.2 L/h [SD: 6.1]) was within the range of values reported in children (34.7 L/h [SD: 11.6]) and adults (45.7 L/h [SD: 9.0]).7

Most adolescents (44/53, 83%) had active symptomatic disease at baseline, and only 4 patients had persistent symptoms at EOS visit. For patients with focal itching, tingling, or tenderness at baseline (46%, 57%, and 57%, respectively), only 1 patient had the symptom at EOS visit. No patient with burning or pain at baseline (23% and 50%, respectively) had the symptom at EOS visit. Two patients without tenderness at baseline and 1 patient without pain at baseline had the symptom at EOS visit. Of the 44 patients with active recurrent herpes labialis at baseline, 43 (98%) had an improved disease status at EOS.

At baseline, erythema was present in 66% of patients and remained for 5 patients (11%) at EOS visit. Papule stage was present in 55% of patients at baseline and 1 patient at EOS visit. Of patients with vesicle, ulcer/soft crust, or hard crust stage at baseline (50%, 16%, and 5%, respectively), all had resolved at EOS visit. Kaplan-Meier analysis revealed a median time to healing of 5.9 days for nonaborted lesions and 5.1 days for aborted and nonaborted lesions. Eight patients (19%) had aborted lesions.

DISCUSSION

To our knowledge, this is the first study in adolescents to evaluate the PK and tolerability of a single dose of famciclovir in adolescent patients with recurrent herpes labialis. Although the study was limited by the small sample size, nonblinding, and no comparator, these preliminary data showed that a single 1500 mg dose of famciclovir appeared to be well tolerated and moderately efficacious in adolescent patients when administered within 24 hours of onset of recurrent herpes labialis. The safety profile and PK appear similar to that previously described in adults and children 6 to 12 years of age. The Cmax, AUC, and t1/2 in adolescents were commensurate with each of these 2 groups.7 These results suggest that the PK of penciclovir in adults and adolescents are dose linear up to a famciclovir dose of 1500 mg.

No conclusions can be made from the exploratory efficacy data and the healing time due to the lack of a control group. In addition, therapy was clinic initiated (ie, median of 21 hours after initiation of symptoms) and not patient initiated (ie, adults self-administered therapy at a median of 1 hour after onset of prodromal symptoms4). Thus, the optimal intervention time was probably missed in most of our patients. Further studies comparing treated and untreated patients are needed.

Regimen complexity, side effects, pill burden, dosing frequency, cost, polypharmacy, and hectic adolescent lifestyles contribute to low adherence. Studies have shown that shorter duration and less frequent dosing improve adherence, with once-daily dosing being optimal.8 Thus, simplified dosing should contribute to improved therapy compliance, patient acceptability, and treatment outcomes. For example, single-dose azithromycin improves adherence in patients with chlamydial urethritis.9 The options for oral antiviral treatment of adolescents with herpes labialis are limited. Valacyclovir is approved treatment in adolescents and adults in a 2-dose regimen of 2 g per dose given 12 hours apart. Single-dose therapy with 1500 mg of famciclovir taken at the first sign/symptom of recurrent herpes labialis is approved treatment in adults. The results of the current study suggest that a single dose of famciclovir may be an acceptable therapeutic option for adolescents too.

ACKNOWLEDGMENTS

The authors thank the volunteers and coinvestigators for their participation in this study, including Mohamed Abudalu, MD, St Louis, MO; David Britt, MD, Longmont, CO; Matthew Davis, MD, Rochester, NY; Steven Elliott, MD, Evansville, IN; Brandon Essink, MD, Omaha, NE; Brian Feaver, MD, Lake Jackson, TX; Helen Henry, MD, Portland, OR; Keith Reisinger, MD, Pittsburgh, PA; and Harvey Resnick, MD, Lake Jackson, TX. Data analysis was performed by Novartis Pharmaceuticals Corporation. Editorial support for the preparation of this manuscript was provided by Lynne Isbell, PhD (Carmel, IN). All authors were involved in revising the draft. Stan Block, MD, and Ram Yogev, MD, received no compensation for the writing of the paper.

REFERENCES

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Keywords:

herpes labialis; adolescent; famciclovir; safety; pharmacokinetics

© 2011 Lippincott Williams & Wilkins, Inc.