Tolvaptan Use in Severe Neonatal Autosomal Dominant Polycystic Kidney Disease (Adpkd): The Pharmaceutical Challenge

Abstract

BackgroundUnlicensed medications are used all the time in the management of diseases in childhood. Tolvaptan (Jinarc®) is a vasopressin V2-receptor antagonist licensed for use to slow the progression of cyst development and renal insufficiency of ADPKD in adults with CKD stage 1 to 3 with evidence of rapidly progressing disease. Studies of animal models implicate the antidiuretic hormone arginine vasopressin and its messenger cyclic adenosine monophosphate (cAMP) as promoters of kidney-cyst cell proliferation and luminal fluid secretion. The suppression of vasopressin release by means of high water intake, genetic elimination of vasopressin, and vasopressin V2-receptor blockade all reduce the cyst burden and protect kidney function1 A Phase 3 trial showed that Tolvaptan, as compared with placebo, slowed down the increase in total kidney volume and decline in kidney function in adults (average 39 yrs) with ADPKD over a 3-year period.2 ADPKD is the most common form of polycystic kidney disease (PKD) typically late in onset and results from mutation of either of two genes: PKD1 and PKD2. Autosomal recessive polycystic kidney (ARPKD), the other form of PKD, is 20 times less common, presents primarily in infancy and childhood, is typically more severe, and commonly associated with hypertension. ARPKD results from mutation of PKHD1. In spite of these differences, there is growing evidence to suggest that ADPKD and ARPKD are more related than previously suspected.3 Bilineal inheritance of PKD1 abnormalities has been reported to cause extremely severe disease resembling ARPKD.4 The use of Tolvaptan in the management of PKD in children is therefore expected to become more important.AimTo describe the first known UK use of Tolvaptan in a neonate with severe ADPKD and the role of the hospital pharmacist in facilitating the use.MethodThe role descriptor of hospital pharmacists produced by the World Health Organisation (WHO) was adapted and used to map the pharmaceutical challenges of using Tolvaptan in this child. The descriptor include: (i) Promotion of rational prescribing of drugs, (ii) Use of specialist pharmacists networks to gain greater expertise; (iii) Monitor compliance and therapeutic response and report adverse drug reactions; (iv) ensure supply of high quality products; (v) partake in planning and implementation of clinical trials.ResultsThe use of Tolvaptan for indication other than hyponatraemia and other endocrine uses are not routinely commissioned by NHS England. In view of the exceptionality of this case – a severe neonatal form of ADPKD with estimated prevalence of the order of 1 in tens of millions, an Individual Funding Request (IFR) application was made and was approved. The application was supported by financial information provided by the hospital pharmacist who facilitated the application process. Using available information and formulation knowledge, a suspension was eventually recommended and was well tolerated. This resulted in approximately 85% reduction in the cost of treatment over six months. T...

Hyponatremia and cyst growth in neonatal polycystic kidney disease: a case for aquaretics?

“…A recent case report in Pediatric Nephrology straddles the indications for the two brands and raises some interesting questions: Gilbert et al report a case of an infant with biallelic PKD1 variants who was treated with tolvaptan [6,7]. In rare instances, like the reported case, the combination of a disease-causing ADPKD mutation on one allele with a hypomorphic variant on the other allele can cause a form of severe neonatal PKD that is mimicking the autosomal recessive form (ARPKD) [8].…”

New Options in ADPKD and How to Use them–the PROPKD Score and Beyond

“…Patients who can´t reach this threshold and whose PROPKD score is >6 should be considered for long-term tolvaptan therapy. In general, the more severe the polycystic kidney disease is the earlier tolvaptan should be administered, which has already been used successfully (offlabel) in a new-born infant with severe polycystic kidney disease ADPKD [19].…”

Tolvaptan in Pediatric Autosomal Dominant Polycystic Kidney Disease: From Here to Where?

“…This suggests the usefulness of tolvaptan for treating severe neonatal PKD. The second case of tolvaptan use is in a neonate with severe ADPKD in the UK; tolvaptan administration relieved edema, but the kidneys remained enlarged [31]. Tolvaptan has also been used to successfully treat pediatric syndrome of inappropriate antidiuretic hormone as well as severe hyponatremia in pediatric nephrotic syndrome [32][33][34].…”

“…Polyuria was found in a female infant treated for severe ADPKD, and there have been no incidents of hypernatremia or hepatotoxicity [30]. While tolvaptan produced the expected aquaresis and blood pressure reduction in another severe neonatal ADPKD case, no AEs were reported [31]. Kerling et al [42] reported 1 case of hypernatremia which was reversible after 1 day in a study of tolvaptan for the treatment of neonates and infants with capillary leak syndrome after cardiac surgery.…”