Sindy C. Moreno

Pharmacokinetics of Oral Valganciclovir and Intravenous Ganciclovir Administered to Prevent Cytomegalovirus Disease in an Adult Patient Receiving Small-Intestine Transplantation

Cytomegalovirus (CMV) is the most common viral pathogen following intestine transplantation, with an overall incidence of 30 to 40% (2). Current prophylactic strategies are center specific and usually include intravenous (i.v.) ganciclovir (GCV) for 6 months. Administration of i.v. GCV is problematic because of the risk of infection associated with the use of a long term-catheter. Oral GCV capsules have a low bioavailability (6%) and limit the drug concentration in serum, which is especially important in these patients. Valganciclovir (VGCV) is a prodrug of GCV. Following oral intake, the great majority of VGCV is rapidly converted to GCV by intestinal and hepatic esterases; no other metabolites have been detected. The absolute bioavailability of GCV from VGCV tablets following oral administration is approximately 60% (3). No data about safety and bioavailability have been reported for the use of VGCV in small-intestine transplant recipients for CMV infection prophylaxis. We report the pharmacokinetic profile of VGCV in an adult patient with a small-intestine transplantat performed because of an intestinal desmoid tumor. The patient was a 23-year-old female. She weighted 50 kg. She was seropositive for CMV and had received an organ from a donor seropositive for CMV. She had a long history on total parenteral nutrition (TPN) requirements. After transplantation, she had an episode of acute cellular rejection resolved by an increase in the doses of the immunosuppressors and a bolus of corticosteroids. She started to eat on day 12 after transplantation, although she received concomitant support by parenteral nutrition until week 8. The immunosuppression regimen was azatioprine, tacrolimus, corticosteroids, and basiliximab. Tacrolimus was changed from the i.v. to the oral route on day 17. The patient received i.v. GCV as CMV prophylaxis while waiting for the approval of VGCV for compassionate use. On month 2 after transplantation, CMV prophylaxis was changed from i.v. GCV to oral VGCV. At the time, she was receiving a diet of 2,600 cal/day, containing 15 to 20% protein, 30 to 35% fat, and 50 to 60% carbohydrate. We obtained scheduled serum samples to measure GCV levels on the last day she received i.v. GCV (5 mg/kg once a day [q.d.]) and also during the first day she received oral VGCV (900 mg q.d.). Before obtaining the samples for GCV levels of i.v. GCV and also for oral VGCV, the patient had a 3-day washout period. The GCV levels were determined by high-performance liquid chromatography as described previously (4). Bioavailability was calculated as follows: [AUC of oral VGCV × i.v. GCV dose (milligrams)]/[AUC of i.v. GCV × oral VGCV dose (milligrams)]. The results are shown in Fig. ​Fig.1.1. The area under the concentration-time curve over 24 h (AUC0-24 h) for i.v. GCV was 35.27 μg · h/ml, and that for oral VGCV was 85.67 μg · h/ml. The maximal drug concentration achieved with i.v. GCV was 14.36 μg/ml, and that obtained with oral VGCV was 9.82 μg/ml. The time to the maximum observed drug concentration was 1 h with i.v. GCV and 6 h with oral VGCV. The absolute bioavailability of GCV derived from 900 mg of oral VGCV administered once daily was 64.7%. FIG. 1. Concentrations of GCV over the 24-h dosing interval after administration of a single dose of i.v. GCV (5 mg/kg) and oral VGCV (900 mg q.d.) determined in serum samples by high-performance liquid chromatography. The patient continued receiving oral VGCV, adjusted to renal function, until month 6 after transplantation. She was monitored monthly by pp65 antigenemia and by scheduled viral culture of small-intestine biopsies, and she did not develop a CMV infection during the first year after transplantation. Oral VGCV has been studied in different populations as prophylaxis and treatment of CMV infection. The bioavailability of oral VGCV is 60%. In liver transplant recipients, the mean AUC of GCV following a single dose of 900 mg of VGCV was greater (41.7 μg · h/ml) (3) than that observed in human immunodeficiency virus-infected patients (24.8 μg · h/ml) (1). Greater AUCs in transplant recipients are probable due to the longer terminal elimination resulting from the use of nephrotoxic immunosuppressive drugs (e.g., tacrolimus). Too large a GCV AUC could lead to an increase in the frequency of hematological and renal toxicity. Preliminary studies have shown that oral VGCV is effective for the prevention of CMV disease, including donor-positive, recipient-negative solid-organ transplant recipients (C. Paya, 42nd Intersci. Conf. Antimicrob. Agents Chemother., abstr. LB-4, 2002). In a study analyzing the pharmacokinetic profile of GCV in a population of solid-organ transplant patients after 100 days of oral administration of VGCV, the average daily systemic exposure (AUC0-24 h) was 40.2 μg · h/ml ± 41. Viremia was totally suppressed during prophylaxis when the GCV AUC0-24 h was >50 μg · h/ml. The development of CMV disease 1 month after prophylaxis ended was reduced with a greater AUC. The development of CMV disease within 1 year of transplantation was 17.6% and was independent of exposure to GCV during prophylaxis. The greater systemic exposure to GCV delivered by VGCV was associated with delayed development of viremia (H. Wiltshire, S. Hirankarn, C. Farrell, and K. Zuideveld, 43rd Intersci. Conf. Antimicrob. Agents Chemother., abstr. A-1794, 2003). However, there are concerns about the absorption of oral VGCV in recipients of small-intestine transplants. Patients with functional grafts are able to be completely weaned from TPN within 4 to 6 weeks postoperatively, although patients may require partial TPN during episodes of rejection and infection. Most patients are started on enteral feeding via a jejunostomy tube within 2 weeks posttransplantation. Adequate absorption is a good indicator of satisfactory function of the transplanted intestine and is determined by serial monitoring of carbohydrate and fat absorption. The ability to maintain a stable and satisfactory tacrolimus (FK-506) level can also be an indicator of adequate absorption. An appropriate tacrolimus level is usually achieved within 1 month posttransplantation (5). Oral VGCV was an effective approach for CMV infection prophylaxis in this patient with an intestinal transplant. This situation represents a challenge for oral therapy because of the difficult absorption and the risk of CMV infection. The levels of GCV while the patients was receiving oral VGC were in the GCV AUC range for efficient suppression of viremia, providing effective prophylaxis of CMV infection. Adjusting the dosing of oral VGCV to creatinine clearance is the best way to avoid renal and hematological toxicity. VGCV may be preferable to GCV for long-term prophylaxis given the ease of administration and the good drug levels in plasma achieved after its administration. The optimal duration of the prophylaxis remains unknown.

How many procedures does it take? Success of a CVS training program for Maternal Fetal Medicine fellows.

To quantify the learning curve for a training program for Maternal Fetal Medicine (MFM) fellows in obtaining successful transvaginal chorionic villus sampling (CVS) results in women with early pregnancy failure (EPF).

Pregnancy-Related Stroke Recurrence at a Regional Referral Center [17H]

INTRODUCTION: To evaluate the risk of perinatal stroke recurrence for women with a history of stroke. METHODS: This is a retrospective cohort study from 2004 to 2014 of pregnant women with a history of stroke attending Thomas Jefferson University Hospital, a regional perinatal and neurosurgical referral center. Using ICD9 codes, pregnancies with a history of stroke were identified. Strokes were stratified into 3 major groups as defined by the American Stroke Association: ischemic, hemorrhagic, and transient ischemic attack (TIA). The primary outcome was pregnancy-relate stroke recurrence. RESULTS: Forty-eight pregnancies in 24 women with a history of stroke were identified. Thirty-one (64.6%) pregnancies had a history of ischemic stroke, 11 (22.9%) had a history of TIA and 6 (12.5%) had a history of hemorrhagic stroke. Antithrombotic treatment, with either aspirin or heparin, was used in 23 (47.9%) pregnancies. Of the 24 women, 1 (4.2%) had stroke recurrence prior to pregnancy compared to one out of 48 pregnancies (2.1%) that occurred 3 days postpartum while not on antithrombotic treatment. Thirty-eight (79.2%) pregnancies resulted in a live birth, 8 (16.7%) resulted in a miscarriage and 2 (4.2%) were ectopic pregnancies. The cesarean section rate for women with a history of hemorrhagic strokes was 100% compared to 25% and 50% for a history of ischemic strokes or TIA, respectively (P<.05). CONCLUSION: Women with a history of stroke appear to have a low risk of stroke recurrence in pregnancy. This study is helpful for informed decision-making regarding future fertility and pregnancy management.

Outcome Differences Between Women With Superimposed Preeclampsia With and Without Severe Features [28Q]

INTRODUCTION: The Hypertension in Pregnancy Task Force (2013) divided the diagnosis of superimposed preeclampsia into two categories: with and without severe features. This study compares obstetric outcomes in women with superimposed preeclampsia with and without severe features based on this new diagnostic criteria. METHODS: Women with singletons and chronic hypertension with superimposed preeclampsia with and without severe features who delivered between January 2008 and July 2015 at a university hospital were identified based on diagnostic criteria in the Hypertension in Pregnancy Task Force (2013). Primary outcome assessed was composite maternal morbidity, including placental abruption, maternal ICU admission, eclampsia, HELLP syndrome and death. Secondary outcomes included gestational age (GA) at delivery, GA at diagnosis, small for GA, birth weight, 5-minute Apgar less than 7, NICU admission, and IUFD. Chi-square and student t test were used as appropriate. RESULTS: 135 pregnancies with severe features and 66 without severe features were identified. Both groups were similar in maternal demographics. There was no difference in the composite maternal morbidity (P=1.0). Women with severe features were delivered earlier (P=.004), had smaller neonates (P=.01), shorter latency from diagnosis to delivery (P=.03), and higher incidence of IUFD (P=.03). Women diagnosed with severe features solely by BP criteria had a significantly higher IUFD rate than the non-severe group (P=.009). CONCLUSION: Women with superimposed preeclampsia and severe features have significantly higher risk of perinatal complications, especially for IUFD. These women warrant intense surveillance.

Predictors of Progression of Preterm Preeclampsia Without Severe Features to Severe Disease [26H]

INTRODUCTION: It is unclear which women will progress from preeclampsia without severe features to more severe disease by delivery. The objective of this study was to evaluate potential predictors of progression from preterm gestational hypertension (GHTN) or preeclampsia (PE) without severe features to severe disease. METHODS: At a university hospital between January 2008 and July 2015, women with singleton pregnancies and GHTN or PE without severe features diagnosed prior to 34 0/7 weeks had demographic and obstetric factors retrospectively collected to determine if those factors influence progression to preeclampsia with severe features. RESULTS: 63 women developed GHTN or PE without severe features less than 34 weeks. 38 women remained without severe features (60.3%), and 25 progressed to PE with severe features (39.7%). There was no difference in age, race, or gestational age at diagnosis or delivery. Smoking (OR 4.7, 95% CI 1.08 to 20.22) and a history of preeclampsia (OR 5.7, 95% CI 1.04 to 30.93) were associated with higher odds of developing severe features. IUGR was associated with a lower risk of progressing to severe features (OR 0.1, 95% CI 0.01 to 0.85). All IUGR patients were delivered for abnormal antenatal testing. Women who developed severe features had lower parity (P=.03) than those without severe features. CONCLUSION: Smoking and history of preeclampsia may be predictors of progression to PE with severe features in women who develop preterm GHTN or PE without severe features. IUGR is associated with lower odds of progression to severe features, likely secondary to earlier delivery for fetal indications.

Monoamniotic Monochorionic Twins-Can They Be Delivered Safely Via Vaginal Route? [9].

INTRODUCTION: Current ACOG technical bulletin #144, 2014 states “Women with monoamniotic twin gestations should undergo cesarean delivery to avoid an umbilical cord complication of the nonpresenting twin at the time of the initial twins delivery.” To assess feasibility of vaginal delivery, we compared neonatal outcomes after attempted VD versus planned cesarean delivery (CD). METHODS: This retrospective cohort study from 2 tertiary-care centers, reviewed all viable MoMo twin pregnancies beyond 24 weeks gestation, delivered over last 15 years. Independent T test and Fisher exact test were used for statistical analysis. RESULTS: Of 29 women with MoMo twins, 15 underwent planned CD and 14 attempted VD. Of the 14 women who attempted VD: 6 underwent IOL; 10 successfully delivered both neonates vaginally with median interval of 3 minutes between the twins; 3 underwent CD for non-reassuring fetal tracing; 1 required CD for the 2nd twin. Despite similar GA at delivery (32.7 vs 33.3 weeks; P=.5) and fetal loss rate (2/15 vs 1/14; P=NS), incidence of intracranial hemorrhage was significantly lower in the vaginally delivered neonates (0 vs 8; P=.006); lower trends were also noted in neonatal length of stay (18 vs 25, P=.09) and respiratory complications. Entangled cords were noted in 28/29 pregnancies at birth. Women with prior CD more often chose repeat CD. Composite maternal outcomes were similar in the 2 groups. CONCLUSION/IMPLICATIONS: VD appears to be safe in appropriately identified MoMo twins. Current practice and recommendations are based on theoretical risks. This study, though small, provides valuable data on option of vaginal delivery for MoMo twins.