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. 2004 May;48(5):1469-87.
doi: 10.1128/AAC.48.5.1469-1487.2004.

Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques

Koen K A Van Rompay  1 , Laurie L Brignolo, Dennis J Meyer, Christopher Jerome, Ross Tarara, Abigail Spinner, Marta Hamilton, Linda L Hirst, David R Bennett, Don R Canfield, Trish G Dearman, Wilhelm Von Morgenland, Phil C Allen, Celia Valverde, Alesha B Castillo, R Bruce Martin, Valerie F Samii, Ray Bendele, John Desjardins, Marta L Marthas, Niels C Pedersen, Norbert Bischofberger
Affiliations

Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques

Koen K A Van Rompay et al. Antimicrob Agents Chemother. 2004 May.

Erratum in

  • Antimicrob Agents Chemother. 2994 Jan;48(6):2346

Abstract

The reverse transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) was previously found to offer strong prophylactic and therapeutic benefits in an infant macaque model of pediatric human immunodeficiency virus (HIV) infection. We now summarize the toxicity and safety of PMPA in these studies. When a range of PMPA doses (4 to 30 mg/kg of body weight administered subcutaneously once daily) was administered to 39 infant macaques for a short period of time (range, 1 day to 12 weeks), no adverse effects on their health or growth were observed; this included a subset of 12 animals which were monitored for more than 2 years. In contrast, daily administration of a high dose of PMPA (30 mg/kg subcutaneously) for prolonged periods of time (>8 to 21 months) to 13 animals resulted in a Fanconi-like syndrome (proximal renal tubular disorder) with glucosuria, aminoaciduria, hypophosphatemia, growth restriction, bone pathology (osteomalacia), and reduced clearance of PMPA. The adverse effects were reversible or were alleviated following either complete withdrawal of PMPA treatment or reduction of the daily regimen from 30 mg/kg to 2.5 to 10 mg/kg subcutaneously. Finally, to evaluate the safety of a prolonged low-dose treatment regimen, two newborn macaques were started on a 10-mg/kg/day subcutaneous regimen; these animals are healthy and have normal bone density and growth after 5 years of daily treatment. In conclusion, our findings suggest that chronic daily administration of a high dose of PMPA results in adverse effects on kidney and bone, while short-term administration of relatively high doses and prolonged low-dose administration are safe.

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Figures

FIG. 1.
FIG. 1.
Induction and reversibility of bone changes following chronic high-dose PMPA treatment. Animal 29003 was started on chronic high-dose PMPA treatment (30 mg/kg per day subcutaneously) at 3 weeks of age for a duration of 21 months. (A) Lateral view of right arm; (B) anterior-posterior view of left leg; (C) lateral view of right leg. For each of these three sets (A to C), the number 1 radiographs were taken at the end of the 21 months of PMPA treatment. Notice the reduced bone opacity and the abnormally widened growth plates (arrows). The number 2 radiographs are from the same animal and were obtained 5 months after PMPA treatment was stopped. Notice the improved bone opacity and normalization of the growth plates.
FIG.2.
FIG.2.
Histopathology of bone and renal tissue of macaques following chronic high-dose PMPA administration. (A, B, D, and E) Distal femur of animal 28214 after 11 months of treatment with PMPA at 30 mg/kg per day subcutaneously. The distal femur growth plate shows diffuse hyperplasia and dysplasia (irregular, thickened, and undulating) (A) with widened trabeculae (B; asterisk). (C) Growth plate of an untreated animal for comparison, with the normal palisades of cartilage and normal process of endochondral bone growth. (D and E) Widened trabeculae of animal 28214 at higher magnifications; notice the wide area of poorly mineralized osteoid (E; double arrow). (F) For comparison, the normal, thin unmineralized osteoid seam adjacent to a layer of osteoblasts (arrowhead) of an untreated animal. (G) Kidney of PMPA-treated animal 29049 (after 16 months of daily subcutaneous administration of PMPA at 30 mg/kg). Notice the severe tubular atrophy and degeneration (indicated by the widened lumen). This animal also had membranoproliferative glomerulonephritis. (H) Kidney of untreated animal for comparison.
FIG. 3.
FIG. 3.
Effects of chronic PMPA treatment on weight gain of infant rhesus macaques. PMPA-treated animals (solid lines) were started on prolonged treatment within the first few weeks after birth, as indicated in Tables 2 and 4. The daily PMPA dosage regimen per kilogram of body weight (administered subcutaneously) is indicated. Two of these animals (animals 29045 and 29276) also received dietary supplements (Diet suppl) that included phosphate, multivitamins, and amino acids, as discussed in the text. Dashed lines indicate the mean ± 1 standard deviation weight of untreated, uninfected sex-matched control animals at the California National Primate Research Center.
FIG. 4.
FIG. 4.
Urinary excretion of phosphorus. Urine was collected over 24 h to estimate the total daily urinary excretion of phosphorus per kilogram of body weight (A), the phosphorus concentration/creatinine concentration ratio (B), and the fractional excretion (FE) value for phosphorus relative to that for creatinine (C). Control data for total daily urinary excretion and the phosphorus concentration/creatinine concentration ratio were obtained from a total of 17 urine samples collected from 11 untreated age-matched animals (age range, 29 to 57 months; three animals were sampled multiple times); fractional excretion values were based on 14 observations for 8 of these untreated animals. Two animals (animals 31121 and 31122) receiving low-dose PMPA (10 mg/kg per day subcutaneously; Table 4) were sampled at 30, 39, 41, 45, and 54 months of age (circles, diamonds, triangles, squares, and multiplications signs, respectively), but fractional excretion values were available only for the 39-, 41-, 45-, and 54-month time points. Animal 31042, which was SIV infected and which received low-dose PMPA (10 mg/kg per day subcutaneously), was sampled at 37 and 39 months of age, with fractional excretion values available only for the 39-month time point. Animal 29046 had been on a high-dose PMPA regimen (30 mg/kg per day subcutaneously) since birth, but the daily dose was reduced to 10 mg/kg at 25 months of age and to 5 mg/kg at 78 months of age (Table 2); 24-h urine collections were performed for animal 29046 at 66 (circle), 75 (square), and 90 (triangle) months of age.
FIG. 5.
FIG. 5.
Radiographic evaluation of animals receiving chronic low-dose PMPA treatment. Three macaques, animals 31042 (SIV infected), 31121 (uninfected), and 31122 (uninfected), received daily subcutaneous treatment with PMPA (10 mg/kg) from the first few weeks of life (Table 4). Radiographs taken at 2.5 years of age were compared to those of three untreated, uninfected age-matched control animals. Animals 30991, 31042, and 31122 are females, while animals 31015, 31111, and 31121 are males. The anterior-posterior (A-P) view of the left (L) knee and the lateral view of the right (R) elbow are given as representative samples. No differences in bone opacity or growth plates were observed between treated and untreated animals.
FIG. 6.
FIG. 6.
DXA scan evaluation of bones in PMPA-treated animals. DXA scans of the femur neck, global proximal femur, distal radius and ulna, and lumbar vertebrae (L2 to L4) were performed. Because each location gave similar results, the bone mineral density of lumbar vertebrae is given as a representative sample. Data for untreated animals are 13 measurements performed for 11 animals (including the two untreated animals whose data are presented in Table 6). Three macaques, animals 31042 (SIV infected), 31121 (uninfected), and 31122 (uninfected), received daily subcutaneous treatment with PMPA (10 mg/kg) from the first few weeks of life (Table 4). For comparison, animals 29276, 29045, and 29046 were started on prolonged high-dose PMPA treatment (30 mg/kg per day subcutaneously) within the first few weeks of life, with dosage reductions starting at 15 to 25 months of age (Table 2). The histories of the 10 animals which received short-term PMPA treatment (animals 30576, 30577, 30581, 30842, 30845, 30339, 30338, 30478, 30007, and 30162) are summarized in Table 1.
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